bluuebunny/crossref_metadata_2025_split huggingface dataset:
EphB3 Is Overexpressed in Non–Small-Cell Lung Cancer and Promotes Tumor Metastasis by Enhancing Cell Survival and Migration
Authors: Ji Xiao-Dan , Li Guo , Feng Yu-Xiong , Zhao Jiang-Sha , Li Jing-Jing , Sun Zhi-Jian , Shi Shuo , Deng Yue-Zhen , Xu Jun-Feng , Zhu Yin-Qiu , Koeffler H. Phillip , Tong Xiang-Jun , Xie Dong 
Published: January 2011

Abstract
Eph receptors, the largest subfamily of transmembrane tyrosine kinase receptors, have been increasingly implicated in various physiologic and pathologic processes, and the roles of the Eph family members during tumorigenesis have recently attracted growing attention. Until now, research on EphB3 function in cancer is limited to focusing on tumor suppression by EphB receptors in colorectal cancer. However, its function in other types of cancer remains poorly investigated. In this study, we explored the function of EphB3 in non–small-cell lung cancer (NSCLC). We found that the expression of EphB3 was significantly upregulated in clinical samples and cell lines, and the expression level correlated with the patient pathologic characteristics, including tumor size, differentiation, and metastasis. Overexpression of EphB3 in NSCLC cell lines accelerated cell growth and migration and promoted tumorigenicity in xenografts in a kinase-independent manner. In contrast, downregulation of EphB3 inhibited cell proliferation and migration and suppressed in vivo tumor growth and metastasis. Furthermore, we showed that silencing of EphB3 inhibited cell growth by reducing DNA synthesis and caspase-8–mediated apoptosis and suppressed cell migration by increasing accumulation of focal adhesion formation. Taken together, our findings suggest that EphB3 provides critical support to the development and progression of NSCLC by stimulating cell growth, migration, and survival, thereby implicating EphB3 as a potential therapeutic target in NSCLC. Cancer Res; 71(3); 1156–66. ©2011 AACR.
ΔNp63α Confers Tumor Cell Resistance to Cisplatin through the AKT1 Transcriptional Regulation
Authors: Sen Tanusree , Sen Nilkantha , Brait Mariana , Begum Shahnaz , Chatterjee Aditi , Hoque Mohammad Obaidul , Ratovitski Edward , Sidransky David 
Published: January 2011

Abstract
Strategies to address resistance to platin drugs are greatly needed in human epithelial cancers (e.g., ovarian, head/neck, and lung) where platins are used widely and resistance occurs commonly. We found that upon ΔNp63α overexpression, AKT1 and phospho-AKT1 levels are upregulated in cancer cells. Investigations using gel-shift, chromatin immunoprecipitation and functional reporter assays implicated ΔNp63α in positive regulation of AKT1 transcription. Importantly, we found that ΔNp63α, AKT1, and phospho-AKT levels are greater in 2008CI3 CDDP-resistant ovarian cancer cells than in 2008 CDDP-sensitive cells. siRNA-mediated knockdown of ΔNp63α expression dramatically decreased AKT1 expression, whereas knockdown of either ΔNp63α or AKT1 decreased cell proliferation and increased death of ovarian and head/neck cancer cells. Conversely, enforced expression of ΔNp63α increased cancer cell proliferation and reduced apoptosis. Together, our findings define a novel ΔNp63α-dependent regulatory mechanism for AKT1 expression and its role in chemotherapeutic resistance of ovarian and head/neck cancer cells. Cancer Res; 71(3); 1167–76. ©2011 AACR.
MicroRNA-1258 Suppresses Breast Cancer Brain Metastasis by Targeting Heparanase
Authors: Zhang Lixin , Sullivan Peggy S. , Goodman Jerry C. , Gunaratne Preethi H. , Marchetti Dario 
Published: January 2011

Abstract
Heparanase (HPSE) is a potent protumorigenic, proangiogenic, and prometastatic enzyme that is overexpressed in brain metastatic breast cancer (BMBC). However, little is known about the regulation of this potential therapeutic target in BMBC, which remains very poorly managed in the clinic. We hypothesized that HPSE gene expression might be regulated by micro RNA that might be exploited therapeutically. Using miRanda and RNAhybrid, we identified miR-1258 as a candidate micro RNA that may directly target HPSE and suppress BMBC. In support of our hypothesis, we found that miR-1258 levels inversely correlated with heparanase expression, enzymatic activity, and cancer cell metastatic propensities, being lowest in highly aggressive BMBC cell variants compared with either nontumorigenic or nonmetastatic human mammary epithelial cells. These findings were validated by analyses of miR-1258 and heparanase content in paired clinical specimens of normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. In regulatory experiments, miR-1258 inhibited the expression and activity of heparanase in BMBC cells, whereas modulating heparanase blocked the phenotypic effects of miR-1258. In functional experiments, stable expression of miR-1258 in BMBC cells inhibited heparanase in vitro cell invasion and experimental brain metastasis. Together, our findings illustrate how micro RNA mechanisms are linked to brain metastatic breast cancer through heparanase control, and they offer a strong rationale to develop heparanase-based therapeutics for treatment of cancer patients with brain metastases, BMBC in particular. Cancer Res; 71(3); 645–54. ©2011 AACR.
Three-Dimensional Culture of Mouse Renal Carcinoma Cells in Agarose Macrobeads Selects for a Subpopulation of Cells with Cancer Stem Cell or Cancer Progenitor Properties
Authors: Smith Barry H. , Gazda Lawrence S. , Conn Bryan L. , Jain Kanti , Asina Shirin , Levine Daniel M. , Parker Thomas S. , Laramore Melissa A. , Martis Prithy C. , Vinerean Horatiu V. , David Eric M. , Qiu Suizhen , Cordon-Cardo Carlos , Hall Richard D. , Gordon Bruce R. , Diehl Carolyn H. , Stenzel Kurt H. , Rubin Albert L. 
Published: January 2011

Abstract
The culture of tumor cell lines in three-dimensional scaffolds is considered to more closely replicate the in vivo tumor microenvironment than the standard method of two-dimensional cell culture. We hypothesized that our method of encapsulating and maintaining viable and functional pancreatic islets in agarose–agarose macrobeads (diameter 6–8 mm) might provide a novel method for the culture of tumor cell lines. In this report we describe and characterize tumor colonies that form within macrobeads seeded with mouse renal adenocarcinoma cells. Approximately 1% of seeded tumor cells survive in the macrobead and over several months form discrete elliptical colonies appearing as tumor cell niches with increasing metabolic activity in parallel to colony size. The tumor colonies demonstrate ongoing cell turnover as shown by BrdU incorporation and activated caspase-3 and TUNEL staining. Genes upregulated in the tumor colonies of the macrobead are likely adaptations to this novel environment, as well as an amplification of G1/S cell-cycle checkpoints. The data presented, including SCA-1 and Oct4 positivity and the upregulation of stem cell–like genes such as those associated with the Wnt pathway, support the notion that the macrobead selects for a subpopulation of cells with cancer stem cell or cancer progenitor properties. Cancer Res; 71(3); 716–24. ©2011 AACR.
Spatial Regulation of RhoA Activity during Pancreatic Cancer Cell Invasion Driven by Mutant p53
Authors: Timpson Paul , McGhee Ewan J. , Morton Jennifer P. , von Kriegsheim Alex , Schwarz Juliane P. , Karim Saadia A. , Doyle Brendan , Quinn Jean A. , Carragher Neil O. , Edward Mike , Olson Michael F. , Frame Margaret C. , Brunton Valerie G. , Sansom Owen J. , Anderson Kurt I. 
Published: January 2011

Abstract
The ability to observe changes in molecular behavior during cancer cell invasion in vivo remains a major challenge to our understanding of the metastatic process. Here, we demonstrate for the first time, an analysis of RhoA activity at a subcellular level using FLIM-FRET (fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer) imaging in a live animal model of pancreatic cancer. In invasive mouse pancreatic ductal adenocarcinoma (PDAC) cells driven by mutant p53 (p53R172H), we observed a discrete fraction of high RhoA activity at both the leading edge and rear of cells in vivo which was absent in two-dimensional in vitro cultures. Notably, this pool of active RhoA was absent in noninvasive p53fl knockout PDAC cells, correlating with their poor invasive potential in vivo. We used dasatanib, a clinically approved anti-invasive agent that is active in this model, to illustrate the functional importance of spatially regulated RhoA. Dasatanib inhibited the activity of RhoA at the poles of p53R172H cells in vivo and this effect was independent of basal RhoA activity within the cell body. Taken together, quantitative in vivo fluorescence lifetime imaging illustrated that RhoA is not only necessary for invasion, but also that subcellular spatial regulation of RhoA activity, as opposed to its global activity, is likely to govern invasion efficiency in vivo. Our findings reveal the utility of FLIM-FRET in analyzing dynamic biomarkers during drug treatment in living animals, and they also show how discrete intracellular molecular pools might be differentially manipulated by future anti-invasive therapies. Cancer Res; 71(3); 747–57. ©2011 AACR.
PTEN Level in Tumor Suppression: How Much Is Too Little?
Authors: Carracedo Arkaitz , Alimonti Andrea , Pandolfi Pier Paolo 
Published: January 2011

Abstract
The importance of PTEN (phosphatase and tensin homolog located on chromosome 10) in cancer has surpassed all predictions and expectations from the time it was discovered and has qualified this gene as one of the most commonly mutated and deleted tumor suppressors in human cancer. PTEN levels are frequently found downregulated in cancer, even in the absence of genetic loss or mutation. PTEN is heavily regulated by transcription factors, microRNAs, competitive endogenous RNAs (such as the PTEN pseudogene), and methylation, whereas the tumor suppressive activity of the PTEN protein can be altered at multiple levels through aberrant phosphorylation, ubiquitination, and acetylation. These regulatory cues are presumed to play a key role in tumorigenesis through the alteration of the appropriate levels, localization, and activity of PTEN. The identification of all these levels of PTEN regulation raises, in turn, a key corollary question: How low should PTEN level(s) or activity drop in order to confer cancer susceptibility at the organismal level? Our laboratory and others have approached this question through the genetic manipulation of Pten in the mouse. This work has highlighted the exquisite and tissue-specific sensitivity to subtle reductions in Pten levels toward tumor initiation and progression with important implications for cancer prevention and therapy. Cancer Res; 71(3); 629–33. ©2011 AACR.
Intracellular CD24 Inhibits Cell Invasion by Posttranscriptional Regulation of BART through Interaction with G3BP
Authors: Taniuchi Keisuke , Nishimori Isao , Hollingsworth Michael A. 
Published: January 2011

Abstract
We report a novel function for the CD24 molecule in pancreatic cancer cells. Intracellular CD24 is associated with stress granules that contain specific mRNAs and RNA-binding proteins that regulate mRNA stability and translation. Intracellular CD24 in stress granules is associated with G3BP, a phosphorylation-dependent endoribonuclease. The vesicles in which the CD24/G3BP complex localizes are transported toward cell protrusions in migrating cells. We show that G3BP binds to and degrades Binder of Arl Two (BART) mRNA. BART was originally identified as a binding partner of ARL2, a small G-protein implicated as a regulator of microtubule dynamics and folding. Intracellular CD24 inhibits the specific endoribonuclease activity of G3BP toward BART mRNA in stress granules. We show that knockdown of CD24 increases retroperitoneal invasion and liver metastasis of pancreatic cancer cells in an orthotopic xenograft model, and that BART also prevents retroperitoneal invasion and liver metastasis of pancreatic cancer cells. Our results imply that surface CD24 may play a role in the inhibition of cell invasion and metastasis, and that intracellular CD24 inhibits invasiveness and metastasis through its influence on the posttranscriptional regulation of BART mRNA levels via G3BP RNase activity. Cancer Res; 71(3); 895–905. ©2011 AACR.
In VivoProfiling of Hypoxic Gene Expression in Gliomas Using the Hypoxia Marker EF5 and Laser-capture Microdissection
Authors: Marotta Diane , Karar Jayashree , Jenkins W. Timothy , Kumanova Monika , Jenkins Kevin W. , Tobias John W. , Baldwin Donald , Hatzigeorgiou Artemis , Alexiou Panagiotis , Evans Sydney M. , Alarcon Rodolfo , Maity Amit , Koch Cameron , Koumenis Constantinos 
Published: January 2011

AbstractHypoxia is a key determinant of tumor aggressiveness, yet little is known regarding hypoxic global gene regulation in vivo. We used the hypoxia marker EF5 coupled with laser-capture microdissection to isolate RNA from viable hypoxic and normoxic regions of 9L experimental gliomas. Through microarray analysis, we identified several mRNAs (including the HIF targets Vegf, Glut-1, and Hsp27) with increased levels under hypoxia compared with normoxia both in vitro and in vivo. However, we also found striking differences between the global in vitro and in vivo hypoxic mRNA profiles. Intriguingly, the mRNA levels of a substantial number of immunomodulatory and DNA repair proteins including CXCL9, CD3D, and RAD51 were found to be downregulated in hypoxic areas in vivo, consistent with a protumorigenic role of hypoxia in solid tumors. Immunohistochemical staining verified increased HSP27 and decreased RAD51 protein levels in hypoxic versus normoxic tumor regions. Moreover, CD8+ T cells, which are recruited to tumors upon stimulation by CXCL9 and CXCL10, were largely excluded from viable hypoxic areas in vivo. This is the first study to analyze the influence of hypoxia on mRNA levels in vivo and can be readily adapted to obtain a comprehensive picture of hypoxic regulation of gene expression and its influence on biological functions in solid tumors. Cancer Res; 71(3); 779–89. ©2011 AACR.
A Unique Spectrum of Somatic PIK3CA (p110α) Mutations Within Primary Endometrial Carcinomas
Authors: Rudd Meghan L. , Price Jessica C. , Fogoros Sarah , Godwin Andrew K. , Sgroi Dennis C. , Merino Maria J. , Bell Daphne W. 
Published: January 2011

Abstract
Purpose: The goal of this study was to comprehensively define the incidence of mutations in all exons of PIK3CA in both endometrioid endometrial cancer (EEC) and nonendometrioid endometrial cancer (NEEC).
Experimental Design: We resequenced all coding exons of PIK3CA and PTEN, and exons 1 and 2 of KRAS, from 108 primary endometrial tumors. Somatic mutations were confirmed by sequencing matched normal DNAs. The biochemical properties of a subset of novel PIK3CA mutations were determined by exogenously expressing wild type and mutant constructs in U2OS cells and measuring levels of AKTSer473 phosphorylation.
Results: Somatic PIK3CA mutations were detected in 52.4% of 42 EECs and 33.3% of 66 NEECs. Half (29 of 58) of all nonsynonymous PIK3CA mutations were in exons 1–7 and half were in exons 9 and 20. The exons 1–7 mutations localized to the ABD, ABD-RBD linker and C2 domains of p110α. Within these regions, Arg88, Arg93, Gly106, Lys111, Glu365, and Glu453, were recurrently mutated; Arg88, Arg93, and Lys111 formed mutation hotspots. The p110α-R93W, -G106R, -G106V, -K111E, -delP449-L455, and -E453K mutants led to increased levels of phospho-AKTSer473 compared to wild-type p110α. Overall, 62% of exons 1–7 PIK3CA mutants and 64% of exons 9–20 PIK3CA mutants were activating; 72% of exon 1–7 mutations have not previously been reported in endometrial cancer.
Conclusions: Our study identified a new subgroup of endometrial cancer patients with activating mutations in the amino-terminal domains of p110α; these patients might be appropriate for consideration in clinical trials of targeted therapies directed against the PI3K pathway. Clin Cancer Res; 17(6); 1331–40. ©2011 AACR.
Phase I Study of Decitabine in Combination with Vorinostat in Patients with Advanced Solid Tumors and Non-Hodgkin's Lymphomas
Authors: Stathis Anastasios , Hotte Sebastien J. , Chen Eric X. , Hirte Holger W. , Oza Amit M. , Moretto Patricia , Webster Sheila , Laughlin Anne , Stayner Lee-Anne , McGill Shauna , Wang Lisa , Zhang Wen-jiang , Espinoza-Delgado Igor , Holleran Julianne L. , Egorin Merrill J. , Siu Lillian L. 
Published: January 2011

Abstract
Purpose: This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat.
Patients and Methods: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied.
Results: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m2/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m2/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m2/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients.
Conclusion: The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types. Clin Cancer Res; 17(6); 1582–90. ©2011 AACR.
ERCC1 and ERCC2 Polymorphisms Predict Clinical Outcomes of Oxaliplatin-Based Chemotherapies in Gastric and Colorectal Cancer: A Systemic Review and Meta-analysis
Authors: Yin Ming , Yan Jingrong , Martinez-Balibrea Eva , Graziano Francesco , Lenz Heinz-Josef , Kim Hyo-Jin , Robert Jacques , Im Seock-Ah , Wang Wei-Shu , Etienne-Grimaldi Marie-Christine , Wei Qingyi 
Published: January 2011

Abstract
Purpose: Nucleotide excision repair (NER) modulates platinum-based chemotherapeutic efficacy by removing drug-produced DNA damage. To summarize published data on the association between polymorphisms of NER genes (ERCC1 and ERCC2) and responses to oxaliplatin-based chemotherapies, we carried out a meta-analysis of gastric and colorectal cancer for commonly studied polymorphisms ERCC1 rs11615C&gt;T and ERCC2 rs13181T&gt;G.
Patients and Methods: In 17 previously published studies, 1,787 cancer patients were treated with the oxaliplatin-based regimen. Primary outcomes included therapeutic response (TR; i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS), and overall survival (OS). We calculated OR or HR with 95% CIs to estimate the risk or hazard.
Results: We found consistent and clinically substantial risk or hazard for TR, PFS, and OS in the oxaliplatin-treated gastric and colorectal cancer patients with an ethnic discrepancy. For ERCC1 rs11615C&gt;T, the T allele was associated with reduced response and poor PFS and OS in Asians (TR: OR = 0.53 and 95% CI = 0.35–0.81; PFS: HR = 1.69 and 95% CI = 1.05–2.70; and OS: HR = 2.03 and 95% CI = 1.60–2.59). For ERCC2 rs13181T&gt;G, the G allele was associated with reduced response and poor PFS and OS in Caucasians (TR: OR = 0.56 and 95% CI = 0.35–0.88; PFS: HR = 1.41 and 95% CI = 1.02–1.95; and OS: HR = 1.42 and 95% CI = 1.11–1.81).
Conclusions: NER ERCC1 rs11615C&gt;T and ERCC2 rs13181T&gt;G polymorphisms are useful prognostic factors in oxaliplatin-based treatment of gastric and colorectal cancer. Larger studies and further clinical trials are warranted to confirm these findings. Clin Cancer Res; 17(6); 1632–40. ©2011 AACR.
Response to Combined Molecular Targeting: Defining the Role of P-STAT3
Authors: Egloff Ann Marie , Grandis Jennifer R. 
Published: January 2011

Abstract
Src family kinase (SFK)–targeting agents are currently undergoing clinical investigation for treatment of solid malignancies. Epidermal growth factor receptor (EGFR)–independent phosphorylation of STAT3 (P-STAT3) has been identified as a mechanism of tumor resistance to agents targeting SFK. Tumor P-STAT3 levels may be an important indicator of EGFR- and SKF-targeted antitumor treatment efficacy. Clin Cancer Res; 17(3); 393–5. ©2011 AACR.
The Late Positive Potential Predicts Subsequent Interference with Target Processing
Authors: Weinberg Anna , Hajcak Greg 
Published: January 2011

AbstractThe current study investigated the association between neural engagement with task-irrelevant images and subsequent interference with target processing using the Emotional Interrupt paradigm [Mitchell, D., Richell, R., Leonard, A., & Blair, R. Emotion at the expense of cognition: Psychopathic individuals outperform controls on an operant response task. Journal of Abnormal Psychology, 115, 559, 2006]. Consistent with previous studies, PCA-derived factors corresponding to the early posterior negativity, P300, and late positive potential (LPP) were enhanced for emotional (i.e., both unpleasant and pleasant) compared with neutral distracters, and the P300 elicited by targets was smaller following emotional compared with neutral pictures. In addition, RTs were increased to targets that followed emotional pictures. Within-subject analyses demonstrated that slow trials were characterized by a smaller P300 and were preceded by pictures with a larger LPP. Additionally, between-subject analyses indicate that individuals with a larger LPP also demonstrated slower RTs to targets and reduced target-elicited P300s. All results were specific to the LPP and were not observed for either the early posterior negativity or the P300 elicited by task-irrelevant pictures. By relating the LPP to subsequent behavioral and ERP interference in both within- and between-subject analyses, the current study provides direct support for the notion that LPP indexes attentional engagement with visual stimuli that is uniquely associated with subsequent interference in terms of both RT slowing and P300 reduction to targets.
Neural Processing of What and Who Information in Speech
Authors: Chandrasekaran Bharath , Chan Alice H. D. , Wong Patrick C. M. 
Published: January 2011

Abstract
Human speech is composed of two types of information, related to content (lexical information, i.e., “what” is being said [e.g., words]) and to the speaker (indexical information, i.e., “who” is talking [e.g., voices]). The extent to which lexical versus indexical information is represented separately or integrally in the brain is unresolved. In the current experiment, we use short-term fMRI adaptation to address this issue. Participants performed a loudness judgment task during which single or multiple sets of words/pseudowords were repeated with single (repeat) or multiple talkers (speaker-change) conditions while BOLD responses were collected. As reflected by adaptation fMRI, the left posterior middle temporal gyrus, a crucial component of the ventral auditory stream performing sound-to-meaning computations (“what” pathway), showed sensitivity to lexical as well as indexical information. Previous studies have suggested that speaker information is abstracted during this stage of auditory word processing. Here, we demonstrate that indexical information is strongly coupled with word information. These findings are consistent with a plethora of behavioral results that have demonstrated that changes to speaker-related information can influence lexical processing.