bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases
Authors: Raynaud Florence I. , Eccles Suzanne , Clarke Paul A. , Hayes Angela , Nutley Bernard , Alix Sonia , Henley Alan , Di-Stefano Francesca , Ahmad Zahida , Guillard Sandrine , Bjerke Lynn M. , Kelland Lloyd , Valenti Melanie , Patterson Lisa , Gowan Sharon , de Haven Brandon Alexis , Hayakawa Masahiko , Kaizawa Hiroyuki , Koizumi Tomonubu , Ohishi Takahide , Patel Sonal , Saghir Nahid , Parker Peter , Waterfield Mike , Workman Paul 
Published: June 2007

AbstractExtensive evidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. Here, we detail the pharmacologic properties of a prototype of a new series of inhibitors of class I PI3K. PI103 is a potent inhibitor with low IC50 values against recombinant PI3K isoforms p110α (2 nmol/L), p110β (3 nmol/L), p110δ (3 nmol/L), and p110γ (15 nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 μmol/L and exhibited an IC50 of 14 nmol/L against DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity of PI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a wide variety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3K signaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resulted in tumor growth delay in eight different human cancer xenograft models with various PI3K pathway abnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with drug levels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograft models and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivo metabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K and importantly represents a lead for further optimization of this novel class of targeted molecular cancer therapeutic. [Cancer Res 2007;67(12):5840–50]
Platelet Factor-4 Variant Chemokine CXCL4L1 Inhibits Melanoma and Lung Carcinoma Growth and Metastasis by Preventing Angiogenesis
Authors: Struyf Sofie , Burdick Marie D. , Peeters Elke , Van den Broeck Karolien , Dillen Chris , Proost Paul , Van Damme Jo , Strieter Robert M. 
Published: June 2007

AbstractThe platelet factor-4 variant, designated PF-4var/CXCL4L1, is a recently described natural non-allelic gene variant of the CXC chemokine platelet factor-4/CXCL4. PF-4var/CXCL4L1 was cloned, and the purified recombinant protein strongly inhibited angiogenesis. Recombinant PF-4var/CXCL4L1 was angiostatically more active (at nanomolar concentration) than PF-4/CXCL4 in various test systems, including wound-healing and migration assays for microvascular endothelial cells and the rat cornea micropocket assay for angiogenesis. Furthermore, PF-4var/CXCL4L1 more efficiently inhibited tumor growth in animal models of melanoma and lung carcinoma than PF-4/CXCL4 at an equimolar concentration. For B16 melanoma in nude mice, a significant reduction in tumor size and the number of small i.t. blood vessels was obtained with i.t. applied PF-4var/CXCL4L1. For A549 adenocarcinoma in severe combined immunodeficient mice, i.t. PF-4var/CXCL4L1 reduced tumor growth and microvasculature more efficiently than PF-4/CXCL4 and prevented metastasis to various organs better than the angiostatic IFN-inducible protein 10/CXCL10. Finally, in the syngeneic model of Lewis lung carcinoma, PF-4var/CXCL4L1 inhibited tumor growth equally well as monokine induced by IFN-γ (Mig)/CXCL9, also known to attract effector T lymphocytes. Taken together, PF-4var/CXCL4L1 is a highly potent antitumoral chemokine preventing development and metastasis of various tumors by inhibition of angiogenesis. These data confirm the clinical potential of locally released chemokines in cancer therapy. [Cancer Res 2007;67(12):5940–8]
Intratumoral Delivery and Suppression of Prostate Tumor Growth by AttenuatedSalmonella entericaserovartyphimuriumCarrying Plasmid-Based Small Interfering RNAs
Authors: Zhang Ling , Gao Lifang , Zhao Lijuan , Guo Baofeng , Ji Kun , Tian Yong , Wang Jinguo , Yu Hao , Hu Jiadi , Kalvakolanu Dhananjaya V. , Kopecko Dennis J. , Zhao Xuejian , Xu De-Qi 
Published: June 2007

AbstractThe facultative anaerobic, invasive Salmonella enterica serovar typhimurium (S. typhimurium) has been shown to retard the growth of established tumors. We wondered if a more effective antitumor response could be achieved in vivo if these bacteria were used as tools for delivering specific molecular antitumor therapeutics. Constitutively activated transcription factor signal transducer and activator of transcription 3 (STAT3) promotes the survival of a number of human tumors. In this study, we investigated the relative efficacies of attenuated S. typhimurium alone or combined with Stat3-specific small interfering RNA (siRNA) in terms of tumor growth and metastasis. The bacteria preferentially homed into tumors over normal liver and spleen tissues in vivo. S. typhimurium expressing plasmid-based Stat3-specific siRNAs significantly inhibited tumor growth, reduced the number of metastastic organs, and extended the life time for C57BL6 mice bearing an implanted prostate tumor, versus bacterial treatment alone. These results suggest that attenuated S. typhimurium combined with an RNA interference approach might be more effective for the treatment of primary as well as metastatic cancer. [Cancer Res 2007;67(12):5859–64]
A Peptide Selected by Biopanning Identifies the Integrin αvβ6 as a Prognostic Biomarker for Nonsmall Cell Lung Cancer
Authors: Elayadi Anissa N. , Samli Kausar N. , Prudkin Ludmila , Liu Ying-Horng , Bian Aihua , Xie Xian-Jin , Wistuba Ignacio I. , Roth Jack A. , McGuire Michael J. , Brown Kathlynn C. 
Published: June 2007

Abstract
The development of new modes of diagnosis and targeted therapy for lung cancer is dependent on the identification of unique cell surface features on cancer cells and isolation of reagents that bind with high affinity and specificity to these biomarkers. We recently isolated a 20-mer peptide which binds to the lung adenocarcinoma cell line, H2009, from a phage-displayed peptide library. We show here that the cellular receptor for this peptide, TP H2009.1, is the uniquely expressed integrin, αvβ6, and the peptide binding to lung cancer cell lines correlates to integrin expression. The peptide is able to mediate cell-specific uptake of a fluorescent nanoparticle via this receptor. Expression of αvβ6 was assessed on 311 human lung cancer samples. The expression of this integrin is widespread in early-stage nonsmall cell lung carcinoma (NSCLC). Log-rank test and Cox regression analyses show that expression of this integrin is significantly associated with poor patient outcome. Preferential expression is observed in the tumors compared with the surrounding normal lung tissue. Our data indicate that αvβ6 is a prognostic biomarker for NSCLC and may serve as a receptor for targeted therapies. Thus, cell-specific peptides isolated from phage biopanning can be used for the discovery of cell surface biomarkers, emphasizing the utility of peptide libraries to probe the surface of a cell. [Cancer Res 2007;67(12):5889–95]
Tobacco Use, Body Mass Index, and the Risk of Leukemia and Multiple Myeloma: A Nationwide Cohort Study in Sweden
Authors: Fernberg Pia , Odenbro Åsa , Bellocco Rino , Boffetta Paolo , Pawitan Yudi , Zendehdel Kazem , Adami Johanna 
Published: June 2007

Abstract
In a prospective cohort study of more than 330,000 Swedish construction workers, we explored the effect of tobacco smoking, oral moist snuff use, and body mass index (BMI) on the risk of developing leukemia (excluding chronic lymphocytic leukemia) and multiple myeloma (MM). Study subjects were participants of a health surveillance system within the building industry. Record linkage to the nationwide Swedish cancer registry, migration registry, and cause of death registry made a comprehensive follow-up available. A total of 372 incident cases of leukemia and 520 subjects with MM was ascertained. An increase in risk of acute myelogenous leukemia (AML) was observed in current smokers (incidence rate ratio, 1.50; 95% confidence interval, 1.06–2.11). Furthermore, there was an indication of a possible association between smoking intensity and risk of acute lymphocytic leukemia. Results on snuff use as well as BMI showed no association. This study confirms the role of smoking as a risk factor for AML and gives no support to the hypothesis of a role of snuff use or BMI level on the risk of leukemia or MM. [Cancer Res 2007;67(12):5983–6]
Oral Grape Seed Extract Inhibits Prostate Tumor Growth and Progression in TRAMP Mice
Authors: Raina Komal , Singh Rana P. , Agarwal Rajesh , Agarwal Chapla 
Published: June 2007

AbstractProstate cancer chemoprevention is an alternative and potential strategy to control this malignancy. Herein, we evaluated the chemopreventive efficacy of grape seed extract (GSE) against prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice where animals were fed with GSE by oral gavage at 200 mg/kg body weight dose during 4 to 28 weeks of age. Our results showed a significant reduction (46%, P &lt; 0.01) in the weight of genitourinary tract organs in the GSE-fed mice. The GSE-fed group of mice had a higher incidence of prostatic intraepithelial neoplasia but showed strong reduction in the incidence of adenocarcinoma compared with mice in control group. Prostate tissue from the GSE group showed ∼50% (P &lt; 0.001) decrease in proliferating cell nuclear antigen (PCNA)–positive cells and 64% (P &lt; 0.01) reduction in total PCNA protein level compared with the control group; however, GSE increased apoptotic cells by 8-fold. Furthermore, GSE strongly decreased the protein levels of cyclin B1, cyclin A, and cyclin E by 84% (P &lt; 0.05), 96% (P &lt; 0.05), and 89% (P &lt; 0.001), respectively. The protein expression of cyclin-dependent kinases 2 and 6 and Cdc2 was also decreased by more than 90% (P &lt; 0.05) in the prostate from the GSE-fed group. Together, for the first time, we identified that oral GSE inhibits prostate cancer growth and progression in TRAMP mice, which could be mediated via a strong suppression of cell cycle progression and cell proliferation and an increase in apoptosis. [Cancer Res 2007;67(12):5976–82]
Androgen-Induced Wnt Signaling in Preosteoblasts Promotes the Growth of MDA-PCa-2b Human Prostate Cancer Cells
Authors: Liu Xin-Hua , Kirschenbaum Alexander , Yao Shen , Liu Guizhong , Aaronson Stuart A. , Levine Alice C. 
Published: June 2007

Abstract
The high morbidity and mortality associated with prostate cancer (PCa) result from its tendency to metastasize to bone where it produces predominantly osteoblastic lesions. The Wnt signaling pathway plays an important role in embryogenesis, tumorigenesis, osteoblast development, and bone formation. Androgen signaling via the androgen receptor (AR) is critical in both PCa and bone cell growth. We examined the effects of androgens on cell growth and Wnt signaling in the AR-positive MDA-PCa-2b cell line and MC3T3 preosteoblasts, grown alone and in coculture. We show that the potent androgen dihydrotestosterone increases AR expression and transcriptional activity only in the preosteoblasts. Although dihydrotestosterone induced an 80% increase in PCa cell growth when the cells were grown alone, dihydrotestosterone had a more significant effect on MDA-PCa-2b cell proliferation (3.2-fold increase) when the PCa cells were cocultured with preosteoblasts. Dihydrotestosterone addition to preosteoblasts promoted Wnt-dependent transcriptional reporter activity associated with GSK3βS-9 phosphorylation and accumulation of nuclear β-catenin as well as elevated Runx2 expression. In addition, the increased proliferation of PCa cells in coculture with MC3T3 cells in response to dihydrotestosterone was abrogated by the addition of either exogenous DKK-1 or sFRP-1 protein, two naturally occurring Wnt antagonists. Finally, we show that the paracrine growth-promoting effect of androgens is limited to MDA-PCa-2b cells. These data imply that Wnt signaling is involved in the androgen-regulated crosstalk between preosteoblasts and PCa cells and suggest that androgens may stimulate growth of some prostate tumor cells indirectly, via up-regulation of Wnt signaling in bone cells. [Cancer Res 2007;67(12):5747–53]
Expression of DNA Methyltransferase 1 Is Activated by Hepatitis B Virus X Protein via a Regulatory Circuit Involving the p16INK4a-Cyclin D1-CDK 4/6-pRb-E2F1 Pathway
Authors: Jung Jin Kyu , Arora Payal , Pagano Joseph S. , Jang Kyung Lib 
Published: June 2007

Abstract
DNA methyltransferase 1 (DNMT1) is responsible for copying DNA methylation patterns to the daughter strands during DNA replication. Its expression is frequently up-regulated in human tumors, including hepatocellular carcinoma, but the mechanism of overexpression and its biological significance remain unclear. Here, we show that hepatitis B virus X protein (HBx) activates DNMT1 expression via a regulatory circuit involving the p16INK4a-cyclin D1-cyclin-dependent kinase (CDK) 4/6-retinoblastoma protein (pRb)-E2F1 pathway. HBx induced DNA hypermethylation of p16INK4a promoter to repress its expression, which subsequently led to activation of G1-CDKs, phosphorylation of pRb, activation of E2F1, and finally transcriptional activation of DNMT1. Inhibition of DNMT1 activity by either treatment with 5′-Aza-2′dC or introduction of DNMT1 small interfering RNA not only abolished the DNA methylation-mediated p16INK4a repression but also impaired DNMT1 expression itself, suggesting a cross-talk between DNMT1 and p16INK4a. The up-regulation of cyclin D1 by HBx is likely to serve as an initiative impulse for the circuit because it was absolutely required for the activation of DNMT1 expression. We also observed that accumulated DNMT1 via this pathway inactivates E-cadherin expression through promoter hypermethylation. Considering that the pRb-E2F1 pathway is commonly activated in human tumors, activation of this circuit might be widespread and a potential therapeutic target. [Cancer Res 2007;67(12):5771–8]
Transactivation of the Epidermal Growth Factor Receptor by Formylpeptide Receptor Exacerbates the Malignant Behavior of Human Glioblastoma Cells
Authors: Huang Jian , Hu Jinyue , Bian Xiuwu , Chen Keqiang , Gong Wanghua , Dunlop Nancy M. , Howard O.M. Zack , Wang Ji Ming 
Published: June 2007

Abstract
The G protein-coupled formylpeptide receptor (FPR), which mediates leukocyte migration in response to bacterial and host-derived chemotactic peptides, promotes the chemotaxis, survival, and tumorigenesis of highly malignant human glioblastoma cells. Because glioblastoma cells may also express other receptors for growth signals, such as the epidermal growth factor (EGF) receptor (EGFR), we investigated the role of EGFR in the signaling cascade of FPR and how two receptors cross-talk to exacerbate tumor growth. We found that N-formyl-methionyl-leucyl-phenylalanine, an FPR agonist peptide, rapidly induced EGFR phosphorylation at tyrosine residue (Tyr) 992, but not residues 846, 1068, or 1173, in glioblastoma cells, whereas all these residues were phosphorylated after only EGF treatment. The FPR agonist-induced EGFR phosphorylation in tumor cells was dependent on the presence of FPR as well as Gαi proteins, and was controlled by Src tyrosine kinase. The transactivation of EGFR contributes to the biological function of FPR in glioblastoma cells because inhibition of EGFR phosphorylation significantly reduced FPR agonist-induced tumor cell chemotaxis and proliferation. Furthermore, depletion of both FPR and EGFR by short interference RNA abolished the tumorigenesis of the glioblastoma cells. Our study indicates that the glioblastoma-promoting activity of FPR is mediated in part by transactivation of EGFR and the cross-talk between two receptors exacerbates the malignant phenotype of tumor cells. Thus, targeting both receptors may yield antiglioblastoma agents superior to those targeting one of them. [Cancer Res 2007;67(12):5906–13]
In vitro Benzo[a]pyrene Diol Epoxide–Induced DNA Adducts and Risk of Squamous Cell Carcinoma of Head and Neck
Authors: Li Donghui , Wang Li-E , Chang Ping , El-Naggar Adel K. , Sturgis Erich M. , Wei Qingyi 
Published: June 2007

Abstract
In this large confirmatory study of 803 patients with squamous cell carcinoma of head and neck (SCCHN) and 839 controls frequency matched by age, sex, and ethnicity, we further examined potential predictors of benzo[a]pyrene diol epoxide (BPDE)-induced adduct levels and their associations with SCCHN risk. BPDE-DNA adduct levels were determined by the 32P-postlabeling method in peripheral lymphocytes after in vitro challenged by BPDE. We also genotyped for GSTM1 null, GSTT1 null, GSTP1 Ile105Val, and GSTP1 Ala114Val. Potential predictors of BPDE-DNA adducts were evaluated by stratification and multivariate linear regression analyses and the association between adduct levels and SCCHN risk by multivariate logistic regression analyses. We found that mean BPDE-DNA adduct levels (the relative adduct labeling × 107 ± SD) were significantly higher in cases (77.6 ± 111.8) than in controls (57.3 ± 98.3; P &lt; 0.001). Using the median control value (29.22) as a cutoff, 63% of the cases were distributed above this level (adjusted odds ratio, 1.71; 95% confidence interval, 1.39–2.10). A significant dose-response relationship was observed between adduct quartiles and SCCHN risk (Ptrend &lt; 0.001). Multivariate linear regression analysis revealed that ethnicity and smoking were significant predictors of BPDE-DNA adduct levels in controls. In conclusion, we confirmed the previously reported association between in vitro BPDE-induced DNA adduct levels and SCCHN risk, and the assay may help identify individuals at high risk of developing smoking-related cancers. [Cancer Res 2007;67(12):5628–34]
In vivo
19F Magnetic Resonance Spectroscopy and Chemical Shift Imaging of Tri-Fluoro-Nitroimidazole as a Potential Hypoxia Reporter in Solid Tumors
Authors: Procissi Daniel , Claus Filip , Burgman Paul , Koziorowski Jacek , Chapman J. Donald , Thakur Sunitha B. , Matei Cornelia , Ling C. Clifton , Koutcher Jason A. 
Published: June 2007

Abstract
Purpose: 2-Nitro-α-[(2,2,2-trifluoroethoxy)methyl]-imidazole-1-ethanol (TF-MISO) was investigated as a potential noninvasive marker of tissue oxygen levels in tumors using 19F magnetic resonance spectroscopy (MRS) and 19F chemical shift imaging.
Experimental Designs: In vitro data were obtained using high-performance liquid chromatography on tumor cells incubated under varying oxygen conditions to determine the oxygen-binding characteristics. In vivo data were obtained using a well-characterized hypoxic murine breast tumor (MCa), in addition to studies on a rat prostate tumor model (R3327-AT) implanted in nude mice. Detection of intratumor 19F signal from TF-MISO was done using MRS for up to 10 h following a 75 mg/kg i.v. injection. Localized distribution of the compound in the implanted MCa tumor has been imaged using slice-selective two-dimensional chemical shift imaging 6 h after injection.
Results: The in vitro results showed that TF-MISO preferentially accumulates in cells incubated under anoxic conditions. The in vivo 19F MR spectral features (line width and chemical shift) were recorded as a function of time after injection, and the results indicate that the fluorine atoms are indeed sensitive to changes in the local environment while still providing a detectable MR signal. Ex vivo spectra were collected and established the visibility of the 19F signal under conditions of maximum hypoxia. Late time point (&gt;6 h) tumor tissue concentrations, as obtained from 19F MRS, suggest that TF-MISO is reduced and retained in hypoxic tumor. The feasibility of obtaining TF-MISO tumor distribution maps in a reasonable time frame was established.
Conclusions: Based on the results presented herein, it is suggested that TF-MISO has the potential to be a valid magnetic resonance hypoxia imaging reporter for both preclinical hypoxia studies and hypoxia-directed clinical therapy.
PIK3CA Mutations and PTEN Loss Correlate with Similar Prognostic Factors and Are Not Mutually Exclusive in Breast Cancer
Authors: Pérez-Tenorio Gizeh , Alkhori Liza , Olsson Birgit , Waltersson Marie Ahnström , Nordenskjöld Bo , Rutqvist Lars Erik , Skoog Lambert , Stål Olle 
Published: June 2007

Abstract
Purpose: The phosphatidylinositol 3′-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3′-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.
Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.
Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor+ status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor+, small in size, and HER2−. PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.
Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.