bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Nucleolin Targeting Aptamer AS1411 Destabilizes Bcl-2 Messenger RNA in Human Breast Cancer Cells
Authors: Soundararajan Sridharan , Chen Weiwei , Spicer Eleanor K. , Courtenay-Luck Nigel , Fernandes Daniel J. 
Published: April 2008

Abstract
We sought to determine whether nucleolin, a bcl-2 mRNA-binding protein, has a role in the regulation of bcl-2 mRNA stability in MCF-7 and MDA-MB-231 breast cancer cells. Furthermore, we examined the efficacy of the aptamer AS1411 in targeting nucleolin and inducing bcl-2 mRNA instability and cytotoxicity in these cells. AS1411 at 5 μmol/L inhibited the growth of MCF-7 and MDA-MB-231 cells, whereas 20 μmol/L AS1411 had no effect on the growth rate or viability of normal MCF-10A mammary epithelial cells. This selectivity of AS1411 was related to a greater uptake of AS1411 into the cytoplasm of MCF-7 cells compared with MCF-10A cells and to a 4-fold higher level of cytoplasmic nucleolin in MCF-7 cells. Stable siRNA knockdown of nucleolin in MCF-7 cells reduced nucleolin and bcl-2 protein levels and decreased the half-life of bcl-2 mRNA from 11 to 5 hours. Similarly, AS1411 (10 μmol/L) decreased the half-life of bcl-2 mRNA in MCF-7 and MDA-MB-231 cells to 1.0 and 1.2 hours, respectively. In contrast, AS1411 had no effect on the stability of bcl-2 mRNA in normal MCF-10A cells. AS1411 also inhibited the binding of nucleolin to the instability element AU-rich element 1 of bcl-2 mRNA in a cell-free system and in MCF-7 cells. Together, the results suggest that AS1411 acts as a molecular decoy by competing with bcl-2 mRNA for binding to cytoplasmic nucleolin in these breast cancer cell lines. This interferes with the stabilization of bcl-2 mRNA by nucleolin and may be one mechanism by which AS1411 induces tumor cell death. [Cancer Res 2008;68(7):2358–65]
Phosphatase and Tensin Homologue Deleted on Chromosome 10 Deficiency Accelerates Tumor Induction in a Mouse Model of ErbB-2 Mammary Tumorigenesis
Authors: Dourdin Nathalie , Schade Babette , Lesurf Robert , Hallett Michael , Munn Robert J. , Cardiff Robert D. , Muller William J. 
Published: April 2008

Abstract
Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and amplification or elevated expression of ErbB-2 are both involved in human breast cancer. To directly test the importance of these genetic events in mammary tumorigenesis, we have assessed whether mammary-specific disruption of PTEN could cooperate with activation of ErbB-2. Transgenic mice expressing ErbB-2 under the transcriptional control of its endogenous promoter (ErbB-2KI) were interbred with mice carrying conditional PTEN alleles and an MMTV/Cre transgene. Loss of one or both PTEN alleles resulted in a dramatic acceleration of mammary tumor onset and an increased occurrence of lung metastases in the ErbB-2KI strain. Tumor progression in PTEN-deficient/ErbB-2KI strains was associated with elevated ErbB-2 protein levels, which were not due to ErbB-2 amplification or to a dramatic increase in ErbB-2 transcripts. Moreover, the PTEN-deficient/ErbB-2KI–derived mouse mammary tumors display striking morphologic heterogeneity in comparison with the homogeneous pathology of the ErbB-2KI parental strain. Therefore, inactivation of PTEN would not only have a dramatic effect on ErbB-2–induced mammary tumorigenesis but would also lead to the formation of mammary tumors that, in part, display pathologic and molecular features associated with the basal-like subtype of primary human breast cancer. [Cancer Res 2008;68(7):2122–31]
MUC4 Mucin Interacts with and Stabilizes the HER2 Oncoprotein in Human Pancreatic Cancer Cells
Authors: Chaturvedi Pallavi , Singh Ajay P. , Chakraborty Subhankar , Chauhan Subhash C. , Bafna Sangeeta , Meza Jane L. , Singh Pankaj K. , Hollingsworth Michael A. , Mehta Parmender P. , Batra Surinder K. 
Published: April 2008

Abstract
MUC4, a high–molecular weight transmembrane glycoprotein, is overexpressed in pancreatic cancer and is implicated in its pathogenesis. It is a heterodimeric protein containing a large extracellular, heavily glycosylated subunit, MUC4α, and a transmembrane growth factor–like subunit, MUC4β. In the present study, we have shown the interaction of human MUC4 with the receptor tyrosine kinase HER2 in pancreatic adenocarcinoma cells by reciprocal coimmunoprecipitation and cocapping studies. MUC4 colocalized with HER2 at the cell surface and in the cytoplasm. Silencing of MUC4 by transient or stable expression of MUC4-targeted short-interfering RNA led to the down-regulation of HER2 with a concomitant decrease in its phosphorylated form (pY1248-HER2). Further analyses revealed that the MUC4-knockdown–mediated decrease in HER2 expression occurred due to the drop in the stability of the receptor. In MUC4-knockdown pancreatic cancer cells, we also observed a reduced phosphorylation of the focal adhesion kinase and p42/44 mitogen-activated protein kinase, which are downstream effector proteins in HER2 signaling. Our findings add a new dimension to MUC4 function as a modulator of cell signaling and provide mechanistic evidence for its role in pancreatic cancer progression. [Cancer Res 2008;68(7):2065–70]
Mammalian Target of Rapamycin and S6 Kinase 1 Positively Regulate 6-thioguanine-Induced Autophagy
Authors: Zeng Xuehuo , Kinsella Timothy J. 
Published: April 2008

Abstract
DNA mismatch repair (MMR) ensures the fidelity of DNA replication and is required for activation of cell cycle arrest and apoptosis in response to certain classes of DNA damage. We recently reported that MMR is also implicated in initiation of an autophagic response after MMR processing of 6-thioguanine (6-TG). It is now generally believed that autophagy is negatively controlled by mammalian target of rapamycin (mTOR) activity. To determine whether mTOR is involved in 6-TG–induced autophagy, we used rapamycin, a potential anticancer agent, to inhibit mTOR activity. Surprisingly, we find that rapamycin cotreatment inhibits 6-TG–induced autophagy in MMR-proficient human colorectal cancer HCT116 (MLH1+) and HT29 cells as measured by LC3 immunoblotting, GFP-LC3 relocalization, and acridine orange staining. Consistently, short interfering RNA silencing of the 70-kDa ribosomal S6 kinase 1 (S6K1), the downstream effector of mTOR, markedly reduces 6-TG–induced autophagy. Furthermore, we show that inhibition of mTOR by rapamycin induces the activation of Akt as shown by increased Akt phosphorylation at Ser473 and the inhibition of 6-TG–induced apoptosis and cell death. Activated Akt is a well-known inhibitor of autophagy. In conclusion, our data indicate that mTOR-S6K1 positively regulates autophagy after MMR processing of 6-TG probably through its negative feedback inhibition of Akt. [Cancer Res 2008;68(7):2384–90]
Aspirin, NSAID, and Acetaminophen Use and the Risk of Endometrial Cancer
Authors: Viswanathan Akila N. , Feskanich Diane , Schernhammer Eva S. , Hankinson Susan E. 
Published: April 2008

Abstract
To date, no prospective studies have explored the relationship between the use of aspirin, other nonsteroidal anti-inflammatory medications (NSAID), and acetaminophen and endometrial adenocarcinoma. Of the 82,971 women enrolled in a prospective cohort study, 747 developed medical record–confirmed invasive endometrial cancer over a 24-year period. Use of aspirin was ascertained from 1980 to 2004, and for other NSAIDs and acetaminophen, from 1990 to 2004. Cox regression models calculated multivariate relative risks (MV RR), controlling for body mass index (BMI), postmenopausal hormone (PMH) use, and other endometrial cancer risk factors. Currency, duration, and quantity of aspirin were not associated with endometrial cancer risk overall [current use: MV RR, 1.03; 95% confidence interval (CI) 0.83–1.27; &gt;10 years of use: MV RR, 1.01; 95% CI, 0.78–1.30; and cumulative average &gt;7 tablets per week: (MV RR, 1.10; 95% CI, 0.84–1.44)]. However, stratified analyses showed that a lower risk of endometrial cancer among obese (BMI, ≥30 kg/m2) women was seen with current aspirin use (MV RR, 0.66; 95% CI, 0.46–0.95). The greatest risk reduction for current aspirin users was seen in postmenopausal obese women who had never used PMH (MV RR, 0.43; 95% CI, 0.26–0.73). The use of other NSAIDs or acetaminophen was not associated with endometrial cancer. Our data suggest that use of aspirin or other NSAIDs does not play an important role in endometrial cancer risk overall. However, risk was significantly lower for current aspirin users who were obese or who were postmenopausal and had never used PMHs; these subgroup findings require further confirmation. [Cancer Res 2008;68(7):2507–13]
Mutation Frequencies and Spectra in DNA Polymerase η–Deficient Mice
Authors: Busuttil Rita A. , Lin Qingcong , Stambrook Peter J. , Kucherlapati Raju , Vijg Jan 
Published: April 2008

Abstract
The low-fidelity polymerase η (polη) is required for bypass of UV-induced pyrimidine dimers inserting adenine nucleotides opposite these lesions. Mutations in the polη gene are responsible for the genetic defect in xeroderma pigmentosum variant patients. To study if the lack of polη significantly elevates spontaneous mutation frequency in various organs and tissues of the mouse, we crossed polη-deficient mice with transgenic mice harboring a chromosomally integrated lacZ-plasmid reporter construct. In cultured embryonic fibroblasts from the lacZ-polη−/− mice, 2.5 J/m2 UV irradiation induced ∼5-fold more mutations than in cells from lacZ control mice, in which an ∼3-fold increase in mutation frequency was found compared with the normal level. Whereas untreated cells harbored mainly 1-bp deletions, UV induced both transitions and transversions, with the latter type more highly represented in the polη-null cells than in the controls. No difference in mutation induction between the polη-null cells and the wild-type cells was observed after treatment with N-ethyl-N-nitrosourea. Having shown the validity of the lacZ model to accurately identify polη-associated mutagenesis, we then determined the mutant frequency at the lacZ locus in liver, spleen, and small intestine of 12-month-old animals. No differences were found between polη-null, heterozygous, or littermate control mice. We conclude that the polη defect is specific for UV damage and has no effect on in vivo mutagenesis in mice. [Cancer Res 2008;68(7):2081–4]
Mcl-1: A Gateway to TRAIL Sensitization
Authors: Kim Seok-Hyun , Ricci M. Stacey , El-Deiry Wafik S. 
Published: April 2008

Abstract
The proapoptotic cytokine tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is being evaluated presently as a selective anticancer agent, but its limited effects against cancer cell lines has raised some concerns about its ultimate clinical utility. Here, we review recent findings that cancer cell sensitivity to TRAIL is greatly increased when the Bcl-2 family protein Mcl-1 is down-regulated by the Raf/vascular endothelial growth factor kinase inhibitor sorafenib, a Food and Drug Administration–approved cancer drug. Using the TRAIL-sorafenib combination as a tactic to more effectively kill cancer cells may provide an effective tool to attack a variety of human cancers that are largely presently untreatable. [Cancer Res 2008;68(7):2062–4]
Mitogen- and Stress-Activated Kinase 1–Mediated Histone H3 Phosphorylation Is Crucial for Cell Transformation
Authors: Kim Hong-Gyum , Lee Ki Won , Cho Yong-Yeon , Kang Nam Joo , Oh Sang-Muk , Bode Ann M. , Dong Zigang 
Published: April 2008

Abstract
Mitogen- and stress-activated kinase 1 (MSK1) belongs to a family of dual protein kinases that are activated by either extracellular signal-regulated kinase or p38 mitogen-activated protein kinases in response to stress or mitogenic extracellular stimuli. The physiologic role of MSK1 in malignant transformation and cancer development is not well understood. Here, we report that MSK1 is involved in 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced or epidermal growth factor (EGF)–induced neoplastic transformation of JB6 Cl41 cells. H89, a potent inhibitor of MSK1, strongly suppressed TPA-induced or EGF-induced cell transformation. When cells overexpressing wild-type MSK1 were treated with TPA or EGF, colony formation increased substantially compared with untreated cells or cells that did not overexpress MSK1. In contrast, MSK1 COOH terminal or NH2 terminal dead dominant negative mutants dramatically suppressed cell transformation. Introduction of small interfering RNA-MSK1 into JB6 Cl41 cells resulted in suppressed TPA-induced or EGF-induced cell transformation. In addition, cell proliferation was inhibited in MSK1 knockdown cells compared with MSK1 wild-type cells. In wild-type MSK1-overexpressing cells, activator protein (AP-1) activation increased after TPA or EGF stimulation, whereas AP-1 activation decreased in both MSK1 dominant-negative mutants and in MSK1 knockdown cells. Moreover, TPA-induced or EGF-induced phosphorylation of histone H3 at Ser10 was increased in wild-type cells but the induced phosphorylation was abolished in MSK1 dominant-negative mutant or MSK1 knockdown cells. Thus, MSK1 is required for tumor promoter-induced cell transformation through its phosphorylation of histone H3 at Ser10 and AP-1 activation. [Cancer Res 2008;68(7):2538–47]
Early Metabolic Response Evaluation by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Allows In vivo Testing of Chemosensitivity in Gastric Cancer: Long-term Results of a Prospective Study
Authors: Ott Katja , Herrmann Ken , Lordick Florian , Wieder Hinrich , Weber Wolfgang A. , Becker Karen , Buck Andreas K. , Dobritz Martin , Fink Ulrich , Ulm Kurt , Schuster Tibor , Schwaiger Markus , Siewert Jörg-Rüdiger , Krause Bernd J. 
Published: April 2008

Abstract
Purpose: We prospectively evaluated the predictive value of positron emission tomography using fluorine-18 fluorodeoxyglucose (FDG-PET) for in vivo testing of chemosensitivity in locally advanced gastric cancer using an a priori definition of metabolic response (a decrease of &gt;35% of the standard uptake value). The goal of the study was the definition of biologically different groups of patients prior to or early during induction therapy, with special emphasis on FDG non–avid tumors.
Experimental Design: Based on our data, which was published in 2003, at least 36 patients with metabolic response or FDG non–avid tumors had to be recruited for an analysis of the group of FDG non–avid tumors with sufficient statistical power. Seventy-one patients (32 metabolic nonresponders, 17 metabolic responders, and 22 patients with FDG non–avid tumors) underwent FDG-PET at baseline. In FDG-avid tumors, FDG-PET was repeated 14 days after the initiation of chemotherapy.
Results: Metabolic responders (17 of 49) showed a high histopathologic response rate (69%) and a favorable prognosis (median survival not reached), whereas metabolic nonresponders (32 of 49) had a poor prognosis (median survival, 24.1 months) and showed a histopathologic response in 17%. The histopathologic response rate (24%) for FDG-PET non–avid patients showed no significant difference compared with FDG-avid nonresponders (P = 0.72). Survival of FDG non–avid patients was 36.7 months (not significantly different from FDG-avid nonresponders, 24.1 months, P = 0.46).
Conclusion: In locally advanced gastric cancer, three different metabolic groups exist. Response and survival was predicted by PET in FDG-avid tumors. Metabolic response assessment was not possible in FDG non–avid tumors; however, due to unfavorable outcome, therapy modification might also be considered in FDG non–avid tumors.
Integrated Genomic and Transcriptomic Analysis of Ductal Carcinoma In situ of the Breast
Authors: Vincent-Salomon Anne , Lucchesi Carlo , Gruel Nadège , Raynal Virginie , Pierron Gaëlle , Goudefroye Rémi , Reyal Fabien , Radvanyi François , Salmon Rémy , Thiery Jean-Paul , Sastre-Garau Xavier , Sigal-Zafrani Brigitte , Fourquet Alain , Delattre Olivier ,   for the breast cancer study group of the Institut Curie
Published: April 2008

Abstract
Purpose: To gain insight into genomic and trancriptomic subtypes of ductal carcinomas in situ of the breast (DCIS).
Experimental Design: We did a combined phenotypic and genomic analysis of a series of 57 DCIS integrated with gene expression profile analysis for 26 of the 57 cases.
Results: Thirty-two DCIS exhibited a luminal phenotype; 21 were ERBB2 positive, and 4 were ERBB2/estrogen receptor (ER) negative with 1 harboring a bona fide basal-like phenotype. Based on a CGH analysis, genomic types were identified in this series of DCIS with the 1q gain/16q loss combination observed in 3 luminal DCIS, the mixed amplifier pattern including all ERBB2, 12 luminal and 2 ERBB2-/ER- DCIS, and the complex copy number alteration profile encompassing 14 luminal and 1 ERBB2-/ER- DCIS. Eight cases (8 of 57; 14%) presented a TP53 mutation, all being amplifiers. Unsupervised analysis of gene expression profiles of 26 of the 57 DCIS showed that luminal and ERBB2-amplified, ER-negative cases clustered separately. We further investigated the effect of high and low copy number changes on gene expression. Strikingly, amplicons but also low copy number changes especially on 1q, 8q, and 16q in DCIS regulated the expression of a subset of genes in a very similar way to that recently described in invasive ductal carcinomas.
Conclusions: These combined approaches show that the molecular heterogeneity of breast ductal carcinomas exists already in in situ lesions and further indicate that DCIS and invasive ductal carcinomas share genomic alterations with a similar effect on gene expression profile.
A Phase I Pharmacokinetic and Pharmacodynamic Study of TKI258, an Oral, Multitargeted Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors
Authors: Sarker Debashis , Molife Rhoda , Evans T.R. Jeffrey , Hardie Maryon , Marriott Cheryl , Butzberger-Zimmerli Priska , Morrison Rosemary , Fox Judith A. , Heise Carla , Louie Sharianne , Aziz Natasha , Garzon Felix , Michelson Glenn , Judson Ian R. , Jadayel Dalal , Braendle Edgar , de Bono Johann S. 
Published: April 2008

Abstract
Purpose: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258).
Experimental Design: A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule.
Results: Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease &gt;6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels.
Conclusions: The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.
Gene Expression–Based Recurrence Prediction of Hepatitis B Virus–Related Human Hepatocellular Carcinoma
Authors: Woo Hyun Goo , Park Eun Sung , Cheon Jae Hee , Kim Ju Han , Lee Ju-Seog , Park Bum Joon , Kim Won , Park Su Cheol , Chung Young Jin , Kim Byeong Gwan , Yoon Jung-Hwan , Lee Hyo-Suk , Kim Chung Yong , Yi Nam-Joon , Suh Kyung-Suk , Lee Kuhn Uk , Chu In-Sun , Roskams Tania , Thorgeirsson Snorri S. , Kim Yoon Jun 
Published: April 2008

Abstract
Purpose: The poor prognosis of hepatocellular carcinoma (HCC) is, in part, due to the high rate of recurrence even after “curative resection” of tumors. Therefore, it is axiomatic that the development of an effective prognostic prediction model for HCC recurrence after surgery would, at minimum, help to identify in advance those who would most benefit from the treatment, and at best, provide new therapeutic strategies for patients with a high risk of early recurrence.
Experimental Design: For the prediction of the recurrence time in patients with HCC, gene expression profiles were generated in 65 HCC patients with hepatitis B infections.
Result: Recurrence-associated gene expression signatures successfully discriminated between patients at high-risk and low-risk of early recurrence (P = 1.9 × 10−6, log-rank test). To test the consistency and robustness of the recurrence signature, we validated its prognostic power in an independent HCC microarray data set. CD24 was identified as a putative biomarker for the prediction of early recurrence. Genetic network analysis suggested that SP1 and peroxisome proliferator–activated receptor-α might have regulatory roles for the early recurrence of HCC.
Conclusion: We have identified a gene expression signature that effectively predicted early recurrence of HCC independent of microarray platforms and cohorts, and provided novel biological insights into the mechanisms of tumor recurrence.
Population Pharmacokinetic-Pharmacodynamic Model of the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid in Cancer Patients
Authors: Li Jing , Jameson Michael B. , Baguley Bruce C. , Pili Roberto , Baker Sharyn D. 
Published: April 2008

AbstractPurpose: To develop a population pharmacokinetic-pharmacodynamic (PK-PD) model that defines the dose-concentration-effect relationship of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), using plasma 5-hydroxyindole-3-acetic acid (5-HIAA) as a biomarker for the antivascular effect of DMXAA.Experimental Design: The plasma DMXAA and 5-HIAA concentration data were obtained from 124 patients receiving DMXAA monotherapy as a 20-minute i.v. infusion weekly or every 3 weeks at doses of 6 to 4,900 mg/m2. The PK and PD data were analyzed by nonlinear mixed effects modeling with NONMEM version 5.Results: DMXAA concentration-time profiles were well described by a three-compartment model with saturable elimination (Michaelis-Menten kinetics). Body surface area (BSA) and sex were significant covariates on the volume of distribution of the central compartment (V1) and the maximum elimination rate (Vm), respectively. Population estimates for Vm, Km (concentration at which half Vm is achieved), and V1 were 112[1 + 0.474(2 − sex)] μmol/L/h, 102 μmol/L, and 8.19(BSA/1.8)0.857 liters, respectively (sex in Vm is equal to 1 for males and equal to 2 for females). The effect of DMXAA on plasma 5-HIAA was described by the stimulatory Emax model, where population estimates for baseline, Emax, and EC50 were 46.3 μmol/L, 2.62-fold increase of the baseline value, and 631 μmol/L, respectively.Conclusions: DMXAA plasma disposition is characterized by a saturable elimination process. BSA-guided dosing is important. The present PK-PD model, with 5-HIAA as a biomarker, supports the use of DMXAA doses of 1,000 to 2,000 mg/m2 in phase II studies, and provides an example of how PK-PD models can be used to aid in selection of drug doses for phase II evaluation.