bluuebunny/crossref_metadata_2025_split huggingface dataset:
The genetics of recolonization: an analysis of the stock structure of grey seals (Halichoerus grypus) in the northwest Atlantic
Authors: Wood S.A. , Frasier T.R. , McLeod B.A. , Gilbert J.R. , White B.N. , Bowen W.D. , Hammill M.O. , Waring G.T. , Brault S. 
Published: June 2011

Although historically distributed along the northeast coast of the United States (US), grey seals ( Halichoerus grypus (Fabricius, 1791)) were considered locally extinct until the late 1980s when three naturally re-established pupping colonies were discovered. Two large populations in Canada, the Gulf of St. Lawrence (GSL) and Sable Island (SI) seals, are possible sources of immigrants for the recovering US population. To assess the stock structure of grey seals in the northwest Atlantic, tissue samples were collected from Canadian and US populations for genetic analyses. We examined nine highly variable microsatellite loci (n = 158; mean number of alleles per locus = 7.22). When population differentiation was assessed without a priori inference of potential subpopulations, all individuals were placed into one population. Pairwise FSTvalues showed little difference in allele frequencies between the SI and the GSL or the Canadian and the US samples. We sequenced a 319 bp segment of the mitochondrial control region and identified 25 haplotypes (n = 163). Nucleotide diversity was similar at SI, GSL, and the US sites. Based on mtDNA haplotypes, no significant difference was found between the SI and GSL populations or the Canadian and the US populations. Although grey seals are philopatric, our study demonstrated that the genetic structure of the northwest Atlantic grey seal population is not different from the null hypothesis of panmixia.
Survival and growth of the caddisfly Limnephilus flavastellus after predation on toxic eggs of the Rough-skinned Newt (Taricha granulosa)
Authors: Gall B.G. , Brodie E.D. , Brodie E.D. 
Published: June 2011

The Rough-skinned Newt ( Taricha granulosa (Skilton, 1849)) possesses a powerful neurotoxin, tetrodotoxin, in the skin that is secondarily deposited in the ova. Although assumed to serve an antipredator function in the eggs, empirical evidence of the toxin’s role in preventing egg predation is lacking. In this study, we characterized the aquatic macroinvertebrate community at a location sympatric with extremely toxic newts and estimated the abundance of caddisflies. We tested aquatic macroinvertebrates sympatric with toxic newts for their capacity to consume the toxic eggs, and examined the propensity of egg predation and its effect on growth of the only known predator of newt eggs, caddisfly larvae. Limnephilid caddisfly larvae were the only invertebrate observed to consume substantial quantities of toxic newt eggs. Survival and growth of the caddisfly Limnephilus flavastellus Banks, 1918 continued when larvae consumed toxic eggs and did not differ from L. flavastellus that also had access to an alternative food source (detritus). Limnephilus flavastellus that had access to eggs + detritus consumed a similar number of eggs compared with those provided with eggs only. These results, combined with the abundance of caddisflies, suggest that caddisflies are important predators of eggs of T. granulosa.
Changes in the cellular composition of the gill epithelium during the life cycle of a nonparasitic lamprey: functional and evolutionary implications
Authors: Bartels Helmut , Fazekas Ursula , Youson John H. , Potter Ian C. 
Published: June 2011

Several lamprey species form pairs, comprising an anadromous parasitic species and a derivative nonparasitic species that neither leaves fresh water nor feeds as an adult. This paper provides the first description of the radical changes undergone by the cellular composition of the gill epithelium during the major phases in the life cycle of a nonparasitic lamprey (American brook lamprey, Lethenteron appendix (DeKay, 1842) (= Lampetra appendix (DeKay, 1842)) and discusses their potential functional and evolutionary significance. The gill epithelium of the larva of L. appendix contains ammocoete mitochondrion-rich cells (AMRCs), intercalated mitochondrion-rich cells, and pavement cells, as does that of the larva of anadromous parasitic species which likewise lives in fresh water. By the completion of metamorphosis, the AMRCs have disappeared and well-developed chloride cells have been produced, the latter cell type being essential for osmoregulation by its closely related anadromous species in hypertonic environments. By the attainment of sexual maturity, the chloride cells have been lost. Such changes in the timing of chloride cell representation could help account for the ability of some metamorphosing, but not mature individuals of another nonparasitic species ( Lampetra planeri (Bloch, 1784)), to osmoregulate in up to 70% of seawater. The well-developed chloride cells in the nonparasitic L. appendix represent the retention of an ancestral character.
A PRIORI ERROR ESTIMATES FOR ENERGY-BASED QUASICONTINUUM APPROXIMATIONS OF A PERIODIC CHAIN
Authors: ORTNER CHRISTOPH , WANG HAO 
Published: June 2011

We derive a priori error estimates for three prototypical energy-based quasicontinuum (QC) methods: the local QC method, the energy-based QC method, and the quasi-nonlocal QC method. Our analysis decomposes the consistency error into modeling and coarsening errors. While previous results on estimating the modeling error exist, we present a new and simpler proof based on negative-norm estimates. Our stability analysis extends previous results on sharp stability estimates under homogeneous strain to the nonlinear setting. Finally, we present numerical experiments to illustrate the results of our analysis.
FINITE ELEMENT APPROACH TO IMMERSED BOUNDARY METHOD WITH DIFFERENT FLUID AND SOLID DENSITIES
Authors: BOFFI DANIELE , CAVALLINI NICOLA , GASTALDI LUCIA 
Published: June 2011

The Immersed Boundary Method (IBM) has been designed by Peskin for the modeling and the numerical approximation of fluid-structure interaction problems, where flexible structures are immersed in a fluid. In this approach, the Navier–Stokes equations are considered everywhere and the presence of the structure is taken into account by means of a source term which depends on the unknown position of the structure. These equations are coupled with the condition that the structure moves at the same velocity of the underlying fluid. Recently, a finite element version of the IBM has been developed, which offers interesting features for both the analysis of the problem under consideration and the robustness and flexibility of the numerical scheme. Initially, we considered structure and fluid with the same density, as it often happens when dealing with biological tissues. Here we study the case of a structure which can have a density higher than that of the fluid. The higher density of the structure is taken into account as an excess of Lagrangian mass located along the structure, and can be dealt with in a variational way in the finite element approach. The numerical procedure to compute the solution is based on a semi-implicit scheme. In fluid-structure simulations, nonimplicit schemes often produce instabilities when the density of the structure is close to that of the fluid. This is not the case for the IBM approach. In fact, we show that the scheme enjoys the same stability properties as in the case of equal densities.
Clinical Significance of miR-146a in Gastric Cancer Cases
Authors: Kogo Ryunosuke , Mimori Koshi , Tanaka Fumiaki , Komune Shizuo , Mori Masaki 
Published: June 2011

Abstract
Purpose: The profiles of microRNAs change significantly in gastric cancer. MiR-146a is reported to be a tumor suppressor in pancreatic cancer, breast cancer, and prostate cancer. We investigated the clinical significance of miR-146a in gastric cancer, in particular focusing on hypothetical miR-146a target genes, such as epidermal growth factor receptor (EGFR) and interleukin-1 receptor-associated kinase (IRAK1).
Experimental Design: We examined miR-146a levels in 90 gastric cancer samples by q-real-time (qRT)–PCR and analyzed the association between miR-146a levels and clinicopathologic factors and prognosis. The regulation of EGFR and IRAK1 by miR-146a was examined with miR-146a–transfected gastric cancer cells. Moreover, we analyzed the association between miR-146a levels and the G/C single nucleotide polymorphism (SNP) within pre-miR-146a seed sequences in 76 gastric cancer samples, using direct sequencing of genomic DNA.
Results: In 90 clinical samples of gastric cancer, miR-146a levels in cancer tissues were significantly lower than those in the corresponding noncancerous tissue (P &lt; 0.001). Lower levels of miR-146a were associated with lymph node metastasis and venous invasion (P &lt; 0.05). Moreover, a lower level of miR-146a was an independent prognostic factor for overall survival (P = 0.003). Ectopic expression of miR-146a inhibited migration and invasion and downregulated EGFR and IRAK1 expression in gastric cancer cells. In addition, G/C SNP within the pre-miR-146a seed sequence significantly reduced miR-146a levels in the GG genotype compared with the CC genotype.
Conclusions: MiR-146a contains an SNP, which is associated with mature miR-146a expression. MiR-146a targeting of EGFR and IRAK1 is an independent prognostic factor in gastric cancer cases. Clin Cancer Res; 17(13); 4277–84. ©2011 AACR.
Increased Detection Sensitivity for KRAS Mutations Enhances the Prediction of Anti-EGFR Monoclonal Antibody Resistance in Metastatic Colorectal Cancer
Authors: Molinari Francesca , Felicioni Lara , Buscarino Michela , De Dosso Sara , Buttitta Fiamma , Malatesta Sara , Movilia Alessandra , Luoni Marco , Boldorini Renzo , Alabiso Oscar , Girlando Salvatore , Soini Barbara , Spitale Alessandra , Di Nicolantonio Federica , Saletti Piercarlo , Crippa Stefano , Mazzucchelli Luca , Marchetti Antonio , Bardelli Alberto , Frattini Milo 
Published: June 2011

Abstract
Purpose: KRAS mutations represent the main cause of resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC). We evaluated whether highly sensitive methods for KRAS investigation improve the accuracy of predictions of anti-EGFR MoAbs efficacy.
Experimental Design: We retrospectively evaluated objective tumor responses in mCRC patients treated with cetuximab or panitumumab. KRAS codons 12 and 13 were examined by direct sequencing, MALDI-TOF MS, mutant-enriched PCR, and engineered mutant-enriched PCR, which have a sensitivity of 20%, 10%, 0.1%, and 0.1%, respectively. In addition, we analyzed KRAS codon 61, BRAF, and PIK3CA by direct sequencing and PTEN expression by immunohistochemistry.
Results: In total, 111 patients were considered. Direct sequencing revealed mutations in codons 12 and 13 of KRAS in 43/111 patients (39%) and BRAF mutations in 9/111 (8%), with almost all of these occurring in nonresponder patients. Using highly sensitive methods, we identified up to 13 additional KRAS mutations compared with direct sequencing, all occurring in nonresponders. By analyzing PIK3CA and PTEN, we found that of these 13 patients, 7 did not show any additional alteration in the PI3K pathway.
Conclusions: The application of highly sensitive methods for the detection of KRAS mutations significantly improves the identification of mCRC patients resistant to anti-EGFR MoAbs. Clin Cancer Res; 17(14); 4901–14. ©2011 AACR.
Role of CXCR3 Ligands in IL-7/IL-7Rα-Fc–Mediated Antitumor Activity in Lung Cancer
Authors: Andersson Åsa , Srivastava Minu K. , Harris-White Marni , Huang Min , Zhu Li , Elashoff David , Strieter Robert M. , Dubinett Steven M. , Sharma Sherven 
Published: June 2011

AbstractPurpose: We evaluated the utility of chimeric γc homeostatic cytokine, IL-7/IL-7Rα-Fc, to restore host APC (antigen presenting cell) and T cell activities in lung cancer.Experimental Design: Utilizing murine lung cancer models we determined the antitumor efficacy of IL-7/IL-7Rα-Fc. APC, T cell, cytokine analyses, neutralization of CXCL9, CXCL10, and IFNγ were carried out to evaluate the mechanistic differences in the antitumor activity of IL-7/IL-7Rα-Fc in comparison to controls.Results: IL-7/IL-7Rα-Fc administration inhibited tumor growth and increased survival in lung cancer. Accompanying the tumor growth inhibition were increases in APC and T cell activities. In comparison to controls, IL-7/IL-7Rα-Fc treatment of tumor bearing mice led to increased: (i) levels of CXCL9, CXCL10, IFNγ, IL-12 but reduced IL-10 and TGFβ, (ii) tumor macrophage infiltrates characteristic of M1 phenotype with increased IL-12, iNOS but reduced IL-10 and arginase, (iii) frequencies of T and NK cells, (iv) T cell activation markers CXCR3, CD69 and CD127low, (v) effector memory T cells, and (vi) T cell cytolytic activity against parental tumor cells. IL-7/IL-7Rα-Fc treatment abrogated the tumor induced reduction in splenic functional APC activity to T responder cells. The CXCR3 ligands played an important role in IL-7/IL-7Rα-Fc–mediated antitumor activity. Neutralization of CXCL9, CXCL10, or IFNγ reduced CXCR3 expressing activated T cells infiltrating the tumor and abrogated IL-7/IL-7Rα-Fc–mediated tumor growth inhibition.Conclusions: Our findings show that IL-7/IL-7Rα-Fc promotes afferent and efferent antitumor responses in lung cancer. Clin Cancer Res; 17(11); 3660–72. ©2011 AACR.
BRAF Activation Induces Transformation and Then Senescence in Human Neural Stem Cells: A Pilocytic Astrocytoma Model
Authors: Raabe Eric H. , Lim Kah Suan , Kim Julia M. , Meeker Alan , Mao Xing-gang , Nikkhah Guido , Maciaczyk Jarek , Kahlert Ulf , Jain Deepali , Bar Eli , Cohen Kenneth J. , Eberhart Charles G. 
Published: June 2011

Abstract
Purpose: BRAF is frequently activated by gene fusion or point mutation in pilocytic astrocytoma, the most common pediatric brain tumor. We investigated the functional effect of constitutive BRAF activation in normal human neural stem and progenitor cells to determine its role in tumor induction in the brain.
Experimental Design: The constitutively active BRAFV600E allele was introduced into human neurospheres, and its effects on MAPK (mitogen-activated protein kinase) signaling, proliferation, soft agarose colony formation, stem cell phenotype, and induction of cellular senescence were assayed. Immunohistochemistry was used to examine p16INK4a levels in pilocytic astrocytoma.
Results: BRAFV600E expression initially strongly promoted colony formation but did not lead to significantly increased proliferation. BRAFV600E-expressing cells subsequently stopped proliferating and induced markers of oncogene-induced senescence including acidic β-galactosidase, PAI-1, and p16INK4a whereas controls did not. Onset of senescence was associated with decreased expression of neural stem cell markers including SOX2. Primary pilocytic astrocytoma cultures also showed induction of acidic β-galactosidase activity. Immunohistochemical examination of 66 pilocytic astrocytomas revealed p16INK4a immunoreactivity in the majority of cases, but patients with tumors negative for p16INK4a had significantly shorter overall survival.
Conclusions: BRAF activation in human neural stem and progenitor cells initially promotes clonogenic growth in soft agarose, suggesting partial cellular transformation, but oncogene-induced senescence subsequently limits proliferation. Induction of senescence by BRAF may help explain the low-grade pathobiology of pilocytic astrocytoma, whereas worse clinical outcomes associated with tumors lacking p16INK4a expression could reflect failure to induce senescence or an escape from oncogene-induced senescence. Clin Cancer Res; 17(11); 3590–9. ©2011 AACR.
Phase II Study of Abiraterone Acetate in Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer Displaying Bone Flare Discordant with Serologic Response
Authors: Ryan Charles J. , Shah Shreya , Efstathiou Eleni , Smith Matthew R. , Taplin Mary-Ellen , Bubley Glenn J. , Logothetis Christopher J. , Kheoh Thian , Kilian Christine , Haqq Christopher M. , Molina Arturo , Small Eric J. 
Published: June 2011

Abstract
Purpose: Abiraterone is an oral inhibitor of CYP17, which is essential for androgen biosynthesis. This multicenter study assessed its efficacy in patients with castration-resistant prostate cancer (CRPC), without prior chemotherapy or CYP17-targeted therapy, and frequency of bone scans discordant with prostate-specific antigen (PSA) and clinical response.
Experimental Design: Thirty-three patients received abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety. Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist's report indicating “disease progression” in context of a 50% or more decline in PSA level, with scan improvement or stability 3 months later.
Results: A 50% or more decline in PSA level at week 12 was confirmed in 22 of 33 (67%) patients. Declines in PSA level of 50% or more were seen in 26 of 33 (79%) patients. Undetectable PSA levels (≤0.1 ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression were 63 weeks and 16.3 months, respectively. Twenty-three patients were evaluable for bone scan flare. Progression was indicated in radiologist's report in 12 of 23 (52%), and 11 of 12 subsequently showed improvement or stability. As prospectively defined, bone scan flare was observed in 11 of 23 (48%) evaluable patients or 11 of 33 (33%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published abiraterone reports.
Conclusion: Clinical responses to abiraterone plus prednisone were frequent and durable in men with metastatic CRPC. Further investigation is needed to clarify the confounding effect of bone scan flare on patient management and interpretation of results. Clin Cancer Res; 17(14); 4854–61. ©2011 AACR.
Sodium Butyrate Inhibits the Self-Renewal Capacity of Endometrial Tumor Side-Population Cells by Inducing a DNA Damage Response
Authors: Kato Kiyoko , Kuhara Aya , Yoneda Tomoko , Inoue Takafumi , Takao Tomoka , Ohgami Tatsuhiro , Dan Li , Kuboyama Ayumi , Kusunoki Soshi , Takeda Satoru , Wake Norio 
Published: June 2011

Abstract
We previously isolated side-population (SP) cells from a human endometrial cancer cell line, Hec1, and determined that Hec1-SP cells have cancer stem–like cell features. In this study, we isolated SP cells and non-SP (NSP) cells derived from a rat endometrial cell line expressing human [12Val] KRAS (RK12V cells) and determined the SP phenotype. RK12V-SP cells showed self-renewal capacity, the potential to develop into stromal cells, reduced expression levels of differentiation markers, long-term proliferating capacity in cultures, and enhanced tumorigenicity, indicating that RK12V-SP cells have cancer stem–like cell features. RK12V-SP cells also display higher resistance to conventional chemotherapeutic drugs. In contrast, treatment with a histone deacetylases (HDAC) inhibitor, sodium butyrate (NaB), reduced self-renewal capacity and completely suppressed colony formation of RK12V-SP cells in a soft agar. The levels of intracellular reactive oxygen species (ROS) and the number of γH2AX foci were increased by NaB treatment of both RK12V-SP cells and RK12V-NSP cells. The expression levels of γH2AX, p21, p27, and phospho-p38 mitogen-activated protein kinase were enhanced in RK12V-SP cells compared with RK12V-NSP cells. These results imply that treatment with NaB induced production of intracellular ROS and DNA damage in both RK12V-SP and RK12V-NSP cells. Following NaB treatment, DNA damage response signals were enhanced more in RK12V-SP cells than in RK12V-NSP cells. This is the first article on an inhibitory effect of NaB on proliferation of endometrial cancer stem–like cells. HDAC inhibitors may represent an attractive antitumor therapy based upon their inhibitory effects on cancer stem–like cells. Mol Cancer Ther; 10(8); 1430–9. ©2011 AACR.
The ARF Tumor Suppressor Inhibits Tumor Cell Colonization Independent of p53 in a Novel Mouse Model of Pancreatic Ductal Adenocarcinoma Metastasis
Authors: Muniz Viviane Palhares , Barnes J. Matthew , Paliwal Seema , Zhang Xuefeng , Tang Xiaoyun , Chen Songhai , Zamba Kokou D. , Cullen Joseph J. , Meyerholz David K. , Meyers Shari , Davis J. Nathan , Grossman Steven R. , Henry Michael D. , Quelle Dawn E. 
Published: June 2011

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incurable, highly metastatic disease that is largely resistant to existing treatments. A better understanding of the genetic basis of PDAC metastasis should facilitate development of improved therapies. To that end, we developed a novel mouse xenograft model of PDAC metastasis to expedite testing of candidate genes associated with the disease. Human PDAC cell lines BxPC-3, MiaPaCa-2, and Panc-1 stably expressing luciferase were generated and introduced by intracardiac injections into immunodeficient mice to model hematogenous dissemination of cancer cells. Tumor development was monitored by bioluminescence imaging. Bioluminescent MiaPaCa-2 cells most effectively recapitulated PDAC tumor development and metastatic distribution in vivo. Tumors formed in nearly 90% of mice and in multiple tissues, including normal sites of PDAC metastasis. Effects of p14ARF, a known suppressor of PDAC, were tested to validate the model. In vitro, p14ARF acted through a CtBP2-dependent, p53-independent pathway to inhibit MiaPaCa-2–invasive phenotypes, which correlated with reduced tumor cell colonization in vivo. These findings establish a new bioluminescent mouse tumor model for rapidly assessing the biological significance of suspected PDAC metastasis genes. This system may also provide a valuable platform for testing innovative therapies. Mol Cancer Res; 9(7); 867–77. ©2011 AACR.
Cotargeting Cyclin D1 Starts a New Chapter in Lung Cancer Prevention and Therapy
Authors: Kim Edward S. , Lee J. Jack , Wistuba Ignacio I. 
Published: June 2011

Abstract
Lung cancer has limited effective therapy and no effective prevention. Cytotoxic chemotherapy has not improved when combined with the epidermal growth factor receptor (EGFR) inhibitor erlotinib (standard lung cancer therapy) or with the rexinoid bexarotene. Combining erlotinib and bexarotene, however, to cotarget cyclin D1 via the retinoid X receptor and EGFR was active preclinically in KRAS-driven lung cancer cells derived from transgenic mice and in two clinical studies in lung cancer (including wild-type EGFR tumors, with or without KRAS mutations), as reported in this issue of the journal by Dragnev and colleagues (beginning on page 818). These results, along with closely related clinical results of the BATTLE program, support the promise of this cotargeting approach for lung cancer prevention and therapy and of cyclin D1 as a predictive, personalizing marker for it. Cancer Prev Res; 4(6); 779–82. ©2011 AACR.