bluuebunny/crossref_metadata_2025_split huggingface dataset:
ON NICHOLS ALGEBRAS OVER PGL(2, q) AND PSL(2, q)
Authors: FREYRE SEBASTIÁN , GRAÑA MATÍAS , VENDRAMIN LEANDRO 
Published: February 2010

We compute necessary conditions on Yetter–Drinfeld modules over the groups PGL(2, q) = PGL(2, 𝔽q) and PSL(2, q) = PSL(2, 𝔽q) to generate finite-dimensional Nichols algebras. This is a first step towards a classification of pointed Hopf algebras with group of group-likes isomorphic to one of these groups. As a by-product of the techniques developed in this work, we prove that any finite-dimensional pointed Hopf algebra over the Mathieu groups M20 or M21 = PSL(3, 4) is the group algebra.
Generalized IFSs on Noncompact Spaces
Authors: Mihail Alexandru , Miculescu Radu 
Published: February 2010

AbstractThe aim of this paper is to continue the research work that we have done in a previous paper published in this journal (see Mihail and Miculescu, 2008). We introduce the notion of GIFS, which is a family of functions "Equation missing", where "Equation missing" is a complete metric space (in the above mentioned paper the case when "Equation missing" is a compact metric space was studied) and "Equation missing". In case that the functions "Equation missing" are Lipschitz contractions, we prove the existence of the attractor of such a GIFS and explore its properties (among them we give an upper bound for the Hausdorff-Pompeiu distance between the attractors of two such GIFSs, an upper bound for the Hausdorff-Pompeiu distance between the attractor of such a GIFS, and an arbitrary compact set of "Equation missing" and we prove its continuous dependence in the "Equation missing"'s). Finally we present some examples of attractors of GIFSs. The last example shows that the notion of GIFS is a natural generalization of the notion of IFS.
An Ets2-Driven Transcriptional Program in Tumor-Associated Macrophages Promotes Tumor Metastasis
Authors: Zabuawala Tahera , Taffany David A. , Sharma Sudarshana M. , Merchant Anand , Adair Brett , Srinivasan Ruchika , Rosol Thomas J. , Fernandez Soledad , Huang Kun , Leone Gustavo , Ostrowski Michael C. 
Published: February 2010

Abstract
Tumor-associated macrophages (TAM) are implicated in breast cancer metastasis, but relatively little is known about the underlying genes and pathways that are involved. The transcription factor Ets2 is a direct target of signaling pathways involved in regulating macrophage functions during inflammation. We conditionally deleted Ets in TAMs to determine its function at this level on mouse mammary tumor growth and metastasis. Ets2 deletion in TAMs decreased the frequency and size of lung metastases in three different mouse models of breast cancer metastasis. Expression profiling and chromatin immunoprecipitation assays in isolated TAMs established that Ets2 repressed a gene program that included several well-characterized inhibitors of angiogenesis. Consistent with these results, Ets2 ablation in TAMs led to decreased angiogenesis and decreased growth of tumors. An Ets2-TAM expression signature consisting of 133 genes was identified within human breast cancer expression data which could retrospectively predict overall survival of patients with breast cancer in two independent data sets. In summary, we identified Ets2 as a central driver of a transcriptional program in TAMs that acts to promote lung metastasis of breast tumors. Cancer Res; 70(4); 1323–33
Nuclear Janus-Activated Kinase 2/Nuclear Factor 1-C2 Suppresses Tumorigenesis and Epithelial-to-Mesenchymal Transition by Repressing Forkhead Box F1
Authors: Nilsson Jeanette , Helou Khalil , Kovács Anikó , Bendahl Pär-Ola , Bjursell Gunnar , Fernö Mårten , Carlsson Peter , Kannius-Janson Marie 
Published: February 2010

Abstract
Progression to metastasis is the proximal cause of most cancer-related mortality. Yet much remains to be understood about what determines the spread of tumor cells. This paper describes a novel pathway in breast cancer that regulates epithelial-to-mesenchymal transition (EMT), motility, and invasiveness. We identify two transcription factors, nuclear factor 1-C2 (NF1-C2) and Forkhead box F1 (FoxF1), downstream of prolactin/nuclear Janus-activated kinase 2, with opposite effects on these processes. We show that NF1-C2 is lost during mammary tumor progression and is almost invariably absent from lymph node metastases. NF1-C2 levels in primary tumors correlate with better patient survival. Manipulation of NF1-C2 levels by expression of a stabilized version or using small interfering RNA showed that NF1-C2 counteracts EMT, motility, invasiveness, and tumor growth. FoxF1 was found to be a direct repressed target of NF1-C2. We provide the first evidence for a role of FoxF1 in cancer and in the regulation of EMT in cells of epithelial origin. Overexpression of FoxF1 was associated with a mesenchymal phenotype, increased invasiveness in vitro, and enhanced growth of breast carcinoma xenografts in nude mice. The relevance of these findings is strengthened by the correlation between FoxF1 expression and a mesenchymal phenoype in breast cancer cell isolates, consistent with the interpretation that FoxF1 promotes invasion and metastasis. Cancer Res; 70(5); 2020–9
Transcriptional Profiles of CD133+ and CD133− Glioblastoma-Derived Cancer Stem Cell Lines Suggest Different Cells of Origin
Authors: Lottaz Claudio , Beier Dagmar , Meyer Katharina , Kumar Praveen , Hermann Andreas , Schwarz Johannes , Junker Markus , Oefner Peter J. , Bogdahn Ulrich , Wischhusen Jörg , Spang Rainer , Storch Alexander , Beier Christoph P. 
Published: February 2010

Abstract
Glioblastoma multiforme (GBM) is paradigmatic for the investigation of cancer stem cells (CSC) in solid tumors. Growing evidence suggests that different types of CSC lead to the formation of GBM. This has prompted the present comparison of gene expression profiles between 17 GBM CSC lines and their different putative founder cells. Using a newly derived 24-gene signature, we can now distinguish two subgroups of GBM: Type I CSC lines display “proneural” signature genes and resemble fetal neural stem cell (fNSC) lines, whereas type II CSC lines show “mesenchymal” transcriptional profiles similar to adult NSC (aNSC) lines. Phenotypically, type I CSC lines are CD133 positive and grow as neurospheres. Type II CSC lines, in contrast, display (semi-)adherent growth and lack CD133 expression. Molecular differences between type I and type II CSC lines include the expression of extracellular matrix molecules and the transcriptional activity of the WNT and the transforming growth factor-β/bone morphogenetic protein signaling pathways. Importantly, these characteristics were not affected by induced adherence on laminin. Comparing CSC lines with their putative cells of origin, we observed greatly increased proliferation and impaired differentiation capacity in both types of CSC lines but no cancer-associated activation of otherwise silent signaling pathways. Thus, our data suggest that the heterogeneous tumor entity GBM may derive from cells that have preserved or acquired properties of either fNSC or aNSC but lost the corresponding differentiation potential. Moreover, we propose a gene signature that enables the subclassification of GBM according to their putative cells of origin. Cancer Res; 70(5); 2030–40
FOXQ1 Is Overexpressed in Colorectal Cancer and Enhances Tumorigenicity and Tumor Growth
Authors: Kaneda Hiroyasu , Arao Tokuzo , Tanaka Kaoru , Tamura Daisuke , Aomatsu Keiichi , Kudo Kanae , Sakai Kazuko , De Velasco Marco A. , Matsumoto Kazuko , Fujita Yoshihiko , Yamada Yasuhide , Tsurutani Junji , Okamoto Isamu , Nakagawa Kazuhiko , Nishio Kazuto 
Published: February 2010

Abstract
Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family, and it has recently been proposed to participate in gastric acid secretion and mucin gene expression in mice. However, the role of FOXQ1 in humans and especially in cancer cells remains unknown. We found that FOXQ1 mRNA is overexpressed in clinical specimens of colorectal cancer (CRC; 28-fold/colonic mucosa). A microarray analysis revealed that the knockdown of FOXQ1 using small interfering RNA resulted in a decrease in p21CIP1/WAF1 expression, and a reporter assay and a chromatin immunoprecipitation assay showed that p21 was one of the target genes of FOXQ1. Stable FOXQ1-overexpressing cells (H1299/FOXQ1) exhibited elevated levels of p21 expression and inhibition of apoptosis induced by doxorubicin or camptothecin. Although cellular proliferation was decreased in H1299/FOXQ1 cells in vitro, H1299/FOXQ1 cells significantly increased tumorigenicity [enhanced green fluorescent protein (EGFP): 2/15, FOXQ1: 7/15] and enhanced tumor growth (437 ± 301 versus 1735 ± 769 mm3, P &lt; 0.001) in vivo. Meanwhile, stable p21 knockdown of H1299/FOXQ1 cells increased tumor growth, suggesting that FOXQ1 promotes tumor growth independent of p21. Microarray analysis of H1299/EGFP and H1299/FOXQ1 revealed that FOXQ1 overexpression upregulated several genes that have positive roles for tumor growth, including VEGFA, WNT3A, RSPO2, and BCL11A. CD31 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining of the tumor specimens showed that FOXQ1 overexpression mediated the angiogenic and antiapoptotic effect in vivo. In conclusion, FOXQ1 is overexpressed in CRC and enhances tumorigenicity and tumor growth presumably through its angiogenic and antiapoptotic effects. Our findings show that FOXQ1 is a new member of the cancer-related FOX family. Cancer Res; 70(5); 2053–63
Noninvasive Detection of Target Modulation following Phosphatidylinositol 3-Kinase Inhibition Using Hyperpolarized 13C Magnetic Resonance Spectroscopy
Authors: Ward Christopher S. , Venkatesh Humsa S. , Chaumeil Myriam M. , Brandes Alissa H. , VanCriekinge Mark , Dafni Hagit , Sukumar Subramaniam , Nelson Sarah J. , Vigneron Daniel B. , Kurhanewicz John , James C. David , Haas-Kogan Daphne A. , Ronen Sabrina M. 
Published: February 2010

Abstract
Numerous mechanism-based anticancer drugs that target the phosphatidylinositol 3-kinase (PI3K) pathway are in clinical trials. However, it remains challenging to assess responses by traditional imaging methods. Here, we show for the first time the efficacy of hyperpolarized 13C magnetic resonance spectroscopy (MRS) in detecting the effect of PI3K inhibition by monitoring hyperpolarized [1-13C]lactate levels produced from hyperpolarized [1-13C]pyruvate through lactate dehydrogenase (LDH) activity. In GS-2 glioblastoma cells, PI3K inhibition by LY294002 or everolimus caused hyperpolarized lactate to drop to 42 ± 12% and to 76 ± 5%, respectively. In MDA-MB-231 breast cancer cells, hyperpolarized lactate dropped to 71 ± 15% after treatment with LY294002. These reductions were correlated with reductions in LDH activity to 48 ± 4%, 63 ± 4%, and 69 ± 12%, respectively, and were associated with a drop in levels of LDHA mRNA and LDHA and hypoxia-inducible factor-1α proteins. Supporting these findings, tumor growth inhibition achieved by everolimus in murine GS-2 xenografts was associated with a drop in the hyperpolarized lactate-to-pyruvate ratio detected by in vivo MRS imaging, whereas an increase in this ratio occurred with tumor growth in control animals. Taken together, our findings illustrate the application of hyperpolarized 13C MRS of pyruvate to monitor alterations in LDHA activity and expression caused by PI3K pathway inhibition, showing the potential of this method for noninvasive imaging of drug target modulation. Cancer Res; 70(4); 1296–305
miR-31 Ablates Expression of the HIF Regulatory Factor FIH to Activate the HIF Pathway in Head and Neck Carcinoma
Authors: Liu Chung-Ji , Tsai Meng-Miao , Hung Pei-Shih , Kao Shou-Yen , Liu Tsung-Yun , Wu Kou-Juey , Chiou Shih-Hwa , Lin Shu-Chun , Chang Kuo-Wei 
Published: February 2010

Abstract
MicroRNAs (miRNA) are endogenously expressed noncoding RNAs with important biological and pathological functions that are yet to be fully defined. This study investigated alterations in miRNA expression in head and neck squamous cell carcinoma (HNSCC), the incidence of which is rising throughout the world. Initial screening and subsequent analysis identified a panel of aberrantly expressed miRNAs in HNSCC tissues, with miR-31 among the most markedly upregulated. Ectopic expression of miR-31 increased the oncogenic potential of HNSCC cells under normoxic conditions in cell culture or tumor xenografts. Conversely, blocking miR-31 expression reduced the growth of tumor xenografts. The in silico analysis suggested that miR-31 may target the 3′ untranslated region (UTR) of factor-inhibiting hypoxia-inducible factor (FIH), a hypoxia-inducible factor (HIF) regulatory factor that inhibits the ability of HIF to act as a transcriptional regulator under normoxic conditions. In support of this likelihood, miR-31 expression repressed FIH expression and mutations within the predictive miR-31 target site in the FIH 3′ UTR abrogated FIH repression. Furthermore, miR-31 expression increased HIF transactivation activity. We found that FIH suppressed oncogenic phenotypes under normoxic conditions and that this activity was abrogated by functional mutations. Lastly, increased miR-31 expression was correlated with decreased levels of FIH in tumor tissues. Our findings suggest that miR-31 contributes to the development of HNSCC by impeding FIH to activate HIF under normoxic conditions. Cancer Res; 70(4); 1635–44
Activation of the Integrin Effector Kinase Focal Adhesion Kinase in Cancer Cells Is Regulated by Crosstalk between Protein Kinase Cα and the PDZ Adapter Protein mda-9/Syntenin
Authors: Hwangbo Cheol , Kim Jaekyung , Lee Jung Joon , Lee Jeong-Hyung 
Published: February 2010

Abstract
Aberrant adhesion signaling pathways in cancer cells underlie their deadly invasive capabilities. The adhesion-related PDZ adapter protein mda-9/syntenin is a positive regulator of cancer cell progression in breast cancer, melanoma, and other human cancers. In this study, we report that mda-9/syntenin mediates adhesion-mediated activation of protein kinase Cα (PKCα) and focal adhesion kinase (FAK) by fibronectin (FN) in human breast cancer and melanoma cells. FN rapidly stimulated the expression of mda-9/syntenin and the activation of PKCα prior to activation of FAK. Inhibiting PKCα suppressed basal or FN-induced expression of mda-9/syntenin, as well as cell migration and invasion toward FN stimulated by mda-9/syntenin. Several lines of evidence suggested that activation of PKCα and expression of mda-9/syntenin were interdependent. First, mda-9/syntenin inhibition suppressed basal or FN-induced phosphorylation of PKCα at Thr638/641, whereas PKCα inhibition suppressed basal or FN-induced expression of mda-9/syntenin. Second, inhibiting either mda-9/syntenin or PKCα suppressed FN-induced formation of integrin-β1/FAK/c-Src signaling complexes. Third, inhibiting either mda-9/syntenin or PKCα suppressed FN-induced phosphorylation of FAK Tyr397 and c-Src Tyr416 and the induction of downstream effector signals to p38 and mitogen-activated protein kinase, Cdc42, and NF-κB. In summary, our findings offer evidence that mda-9/syntenin acts as a molecular adaptor linking PKCα and FAK activation in a pathway of FN adhesion by human breast cancer and melanoma cells. Cancer Res; 70(4); 1645–55
MK-2461, a Novel Multitargeted Kinase Inhibitor, Preferentially Inhibits the Activated c-Met Receptor
Authors: Pan Bo-Sheng , Chan Grace K.Y. , Chenard Melissa , Chi An , Davis Lenora J. , Deshmukh Sujal V. , Gibbs Jackson B. , Gil Susana , Hang Gaozhen , Hatch Harold , Jewell James P. , Kariv Ilona , Katz Jason D. , Kunii Kaiko , Lu Wei , Lutterbach Bart A. , Paweletz Cloud P. , Qu Xianlu , Reilly John F. , Szewczak Alexander A. , Zeng Qinwen , Kohl Nancy E. , Dinsmore Christopher J. 
Published: February 2010

Abstract
The receptor tyrosine kinase c-Met is an attractive target for therapeutic blockade in cancer. Here, we describe MK-2461, a novel ATP-competitive multitargeted inhibitor of activated c-Met. MK-2461 inhibited in vitro phosphorylation of a peptide substrate recognized by wild-type or oncogenic c-Met kinases (N1100Y, Y1230C, Y1230H, Y1235D, and M1250T) with IC50 values of 0.4 to 2.5 nmol/L. In contrast, MK-2461 was several hundredfold less potent as an inhibitor of c-Met autophosphorylation at the kinase activation loop. In tumor cells, MK-2461 effectively suppressed constitutive or ligand-induced phosphorylation of the juxtamembrane domain and COOH-terminal docking site of c-Met, and its downstream signaling to the phosphoinositide 3-kinase–AKT and Ras–extracellular signal-regulated kinase pathways, without inhibiting autophosphorylation of the c-Met activation loop. BIAcore studies indicated 6-fold tighter binding to c-Met when it was phosphorylated, suggesting that MK-2461 binds preferentially to activated c-Met. MK-2461 displayed significant inhibitory activities against fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor, and other receptor tyrosine kinases. In cell culture, MK-2461 inhibited hepatocyte growth factor/c-Met–dependent mitogenesis, migration, cell scatter, and tubulogenesis. Seven of 10 MK-2461–sensitive tumor cell lines identified from a large panel harbored genomic amplification of MET or FGFR2. In a murine xenograft model of c-Met–dependent gastric cancer, a well-tolerated oral regimen of MK-2461 administered at 100 mg/kg twice daily effectively suppressed c-Met signaling and tumor growth. Similarly, MK-2461 inhibited the growth of tumors formed by s.c. injection of mouse NIH-3T3 cells expressing oncogenic c-Met mutants. Taken together, our findings support further preclinical development of MK-2461 for cancer therapy. Cancer Res; 70(4); 1524–33
NOTCH Signaling Is Required for Formation and Self-Renewal of Tumor-Initiating Cells and for Repression of Secretory Cell Differentiation in Colon Cancer
Authors: Sikandar Shaheen S. , Pate Kira T. , Anderson Scott , Dizon Diana , Edwards Robert A. , Waterman Marian L. , Lipkin Steven M. 
Published: February 2010

Abstract
NOTCH signaling is critical for specifying the intestinal epithelial cell lineage and for initiating colorectal adenomas and colorectal cancers (CRC). Based on evidence that NOTCH is important for the maintenance and self-renewal of cancer-initiating cells in other malignancies, we studied the role of NOTCH signaling in colon cancer–initiating cells (CCIC). Tumors formed by CCICs maintain many properties of the primary CRCs from which they were derived, such as glandular organization, cell polarity, gap junctions, and expression of characteristic CRC molecular markers. Furthermore, CCICs have the property of self-renewal. In this study, we show that NOTCH signaling is 10- to 30-fold higher in CCIC compared with widely used colon cancer cell lines. Using small-molecule inhibition and short hairpin RNA knockdown, we show that NOTCH prevents CCIC apoptosis through repression of cell cycle kinase inhibitor p27 and transcription factor ATOH1. NOTCH is also critical to intrinsic maintenance of CCIC self-renewal and the repression of secretory cell lineage differentiation genes such as MUC2. Our findings describe a novel human cell system to study NOTCH signaling in CRC tumor initiation and suggest that inhibition of NOTCH signaling may improve CRC chemoprevention and chemotherapy. Cancer Res; 70(4); 1469–78
A Placental Growth Factor Variant Unable to Recognize Vascular Endothelial Growth Factor (VEGF) Receptor-1 Inhibits VEGF-Dependent Tumor Angiogenesis via Heterodimerization
Authors: Tarallo Valeria , Vesci Loredana , Capasso Onofrio , Esposito Maria Teresa , Riccioni Teresa , Pastore Lucio , Orlandi Augusto , Pisano Claudio , De Falco Sandro 
Published: February 2010

AbstractAngiogenesis is one of the crucial events for cancer development and growth. Two members of the vascular endothelial growth factor (VEGF) family, VEGF-A and placental growth factor (PlGF), which are able to heterodimerize if coexpressed in the same cell, are both required for pathologic angiogenesis. We have generated a PlGF1 variant, named PlGF1-DE in which the residues Asp72 and Glu73 were substituted with Ala, which is unable to bind and activate VEGF receptor-1 but is still able to heterodimerize with VEGF. Here, we show that overexpression in tumor cells by adenoviral delivery or stable transfection of PlGF1-DE variant significantly reduces the production of VEGF homodimer via heterodimerization, determining a strong inhibition of xenograft tumor growth and neoangiogenesis, as well as significant reduction of vessel lumen and stabilization, and monocyte-macrophage infiltration. Conversely, the overexpression of PlGF1wt, also reducing the VEGF homodimer production comparably with PlGF1-DE variant through the generation of VEGF/PlGF heterodimer, does not inhibit tumor growth and vessel density compared with controls but induces increase of vessel lumen, vessel stabilization, and monocyte-macrophage infiltration. The property of PlGF and VEGF-A to generate heterodimer represents a successful strategy to inhibit VEGF-dependent angiogenesis. The PlGF1-DE variant, and not PlGF1wt as previously reported, acts as a “dominant negative” of VEGF and is a new candidate for antiangiogenic gene therapy in cancer treatment. Cancer Res; 70(5); 1804–13
Regulation of p53 Family Member Isoform ΔNp63α by the Nuclear Factor-κB Targeting Kinase IκB Kinase β
Authors: Chatterjee Aditi , Chang Xiaofei , Sen Tanusree , Ravi Rajani , Bedi Atul , Sidransky David 
Published: February 2010

Abstract
The p53 family gene p63 plays an instrumental role in cellular stress responses including responses to DNA damage. In addition to encoding a full-length transcriptional activator, p63 also encodes several dominant inhibitory isoforms including the isoform ΔNp63α, the function of which is not fully understood. ΔNp63α is degraded in response to DNA damage, thereby enabling an effective cellular response to genotoxic agents. Here, we identify a key molecular mechanism underlying regulation of ΔNp63α expression in response to chemotherapeutic agents or tumor necrosis factor-α. We found that ΔNp63α interacts with IκB kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit, IKKγ. The IKKβ kinase promotes ubiquitin-mediated proteasomal degradation of ΔNp63α, whereas a kinase-deficient mutant IKKβ-K44A fails to do so. Cytokine- or chemotherapy-induced stimulation of IKKβ caused degradation of ΔNp63α and augmented transactivation of p53 family–induced genes involved in the cellular response to DNA damage. Conversely, IKKβ inhibition attenuated cytokine- or chemotherapy-induced degradation of ΔNp63α. Our findings show that IKKβ plays an essential role in regulating ΔNp63α in response to extrinsic stimuli. IKK activation represents one mechanism by which levels of ΔNp63α can be reduced, thereby rendering cells susceptible to cell death in the face of cellular stress or DNA damage. Cancer Res; 70(4); 1419–29