bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ligand-Dependent Platelet-Derived Growth Factor Receptor (PDGFR)-α Activation Sensitizes Rare Lung Cancer and Sarcoma Cells to PDGFR Kinase Inhibitors
Authors: McDermott Ultan , Ames Rachel Y. , Iafrate A. John , Maheswaran Shyamala , Stubbs Hannah , Greninger Patricia , McCutcheon Kaitlin , Milano Randy , Tam Angela , Lee Diana Y. , Lucien Laury , Brannigan Brian W. , Ulkus Lindsey E. , Ma Xiao-Jun , Erlander Mark G. , Haber Daniel A. , Sharma Sreenath V. , Settleman Jeffrey 
Published: April 2009

Abstract
Platelet-derived growth factor (PDGF) receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor, c-KIT, and PDGFR, and has shown clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 of 637 tested human tumor-derived cell lines show significant sensitivity to single-agent sunitinib exposure. These two cell lines [a non–small-cell lung cancer (NSCLC) and a rhabdomyosarcoma] showed expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adenosquamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar codependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to gastrointestinal stromal tumors, rare tumors that show PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition. [Cancer Res 2009;69(9):3937–46]
Gonadotropin-Releasing Hormone Type II Induces Apoptosis of Human Endometrial Cancer Cells by Activating GADD45α
Authors: Wu Hsien-Ming , Cheng Jung-Chien , Wang Hsin-Shih , Huang Hong-Yuan , MacCalman Colin D. , Leung Peter C.K. 
Published: April 2009

Abstract
Gonadotropin-releasing hormone type II (GnRH-II) has an antiproliferative effect on human endometrial cancer cells. Apoptosis in cancer cells may play a critical role in regulating cell proliferation. However, more studies are necessary to elucidate the underlying molecular mechanisms and develop potential applications of GnRH-II. Therefore, we explored the mechanisms of GnRH-II–induced apoptosis and the effects of GnRH-II on GADD45α activation in human endometrial cancer cell lines. GnRH-II decreased cell viability in a dose- and time-dependent manner. Apoptosis was induced with increased terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling apoptotic cells after GnRH-II treatment. Knockdown of the endogenous GnRH-I receptor with small interfering RNA (siRNA) rescued the cells from GnRH-II–mediated cell growth inhibition and abolished the induction of apoptosis. GnRH-II activated extracellular signal–regulated kinase (ERK)-1/2 and p38 mitogen-activated protein kinase (MAPK) in a time-dependent manner, and the activation was abolished by GnRH-I receptor siRNA and MAPK inhibitors. Cells pretreated with MAPK inhibitors were rescued from GnRH-II–mediated cell growth inhibition. Moreover, both inhibitors abolished GnRH-II–induced apoptosis. GnRH-II induced GADD45α expression, which was abolished by knockdown of endogenous GnRH-I receptors and MAPK inhibitors. GnRH-II–stimulated cell growth inhibition was rescued by knockdown of endogenous GADD45α with siRNA. Cells treated with GADD45α siRNA were refractory to GnRH-II–induced apoptosis. Thus, GnRH-II inhibits cell growth by inducing apoptosis through binding of the GnRH-I receptor, activation of the ERK1/2 and p38 MAPK pathways, and induction of GADD45α signaling. This finding may provide a new concept relating to the mechanism of GnRH-II–induced antiproliferation and apoptosis in endometrial cancer cells, indicating the possibility of GnRH-II as a promising therapeutic intervention for human endometrial cancer. [Cancer Res 2009;69(10):4202–8]
Silibinin Feeding Alters the Metabolic Profile in TRAMP Prostatic Tumors: 1H-NMRS–Based Metabolomics Study
Authors: Raina Komal , Serkova Natalie J. , Agarwal Rajesh 
Published: April 2009

Abstract
Herein, we evaluated for the first time silibinin efficacy on prostate cancer (PCa) metabolism in transgenic adenocarcinoma of the mouse prostate (TRAMP) model using quantitative high-resolution proton nuclear magnetic resonance spectroscopy metabolomics. Prostate tissues were from mice fed control or silibinin diet for 20 weeks. Comparative metabolic profiling indicated that antitumor effect of silibinin is accompanied by alteration in metabolic profile of TRAMP prostatic tumors as indicated by 6-fold (P = 0.016) increase in glucose content and 48% (P = 0.015) reduction in lactate levels. Increase in citrate use by prostate tissue also reversed with silibinin, as indicated by 3-fold (P = 0.01) increase in citrate levels in silibinin-fed group. Also, 61% and 50% (P &lt; 0.01) decrease in cholesterol and phosphatidylcholine levels, respectively, was observed with silibinin. These results corroborate our earlier findings regarding PCa chemopreventive potential of silibinin in TRAMP model and warrant additional metabolic profiling in other silibinin-fed PCa tumor model tissues. This will help identify specific metabolic biomarkers altered during silibinin treatment, which when detected in clinical biopsies or noninvasive magnetic resonance spectroscopic studies could help monitor silibinin effectiveness against PCa malignancy. [Cancer Res 2009;69(9):3731–5]
Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening
Authors: Woo Hyun Goo , Park Eun Sung , Lee Ju-Seog , Lee Yun-Han , Ishikawa Tsuyoshi , Kim Yoon Jun , Thorgeirsson Snorri S. 
Published: April 2009

Abstract
Genomic copy number aberrations and corresponding transcriptional deregulation in the cancer genome have been suggested to have regulatory roles in cancer development and progression. However, functional evaluation of individual genes from lengthy lists of candidate genes from genomic data sets presents a significant challenge. Here, we report effective gene selection strategies to identify potential driver genes based on systematic integration of genome scale data of DNA copy numbers and gene expression profiles. Using regional pattern recognition approaches, we discovered the most probable copy number–dependent regions and 50 potential driver genes. At each step of the gene selection process, the functional relevance of the selected genes was evaluated by estimating the prognostic significance of the selected genes. Further validation using small interference RNA–mediated knockdown experiments showed proof-of-principle evidence for the potential driver roles of the genes in hepatocellular carcinoma progression (i.e., NCSTN and SCRIB). In addition, systemic prediction of drug responses implicated the association of the 50 genes with specific signaling molecules (mTOR, AMPK, and EGFR). In conclusion, the application of an unbiased and integrative analysis of multidimensional genomic data sets can effectively screen for potential driver genes and provides novel mechanistic and clinical insights into the pathobiology of hepatocellular carcinoma. [Cancer Res 2009;69(9):4059–66]
The Lack of Epithelial Interleukin-7 and BAFF/BLyS Gene Expression in Prostate Cancer as a Possible Mechanism of Tumor Escape from Immunosurveillance
Authors: Di Carlo Emma , D'Antuono Tommaso , Pompa Paolo , Giuliani Rossella , Rosini Sandra , Stuppia Liborio , Musiani Piero , Sorrentino Carlo 
Published: April 2009

AbstractPurpose: The human prostate is endowed with intraepithelial and stromal lymphocytes, which may develop lymphoid follicles (LF) and allow a local immune response. We sought to investigate whether interleukin (IL)-7 and BAFF/BLyS, two fundamental survival factors for T and B cells, are expressed in the normal and neoplastic prostate and affect intraprostatic lymphocyte homeostasis.Experimental Design: We have used real-time reverse transcription-PCR of microdissected prostatic glands and confocal microscopy to detect cytokine production, combined with immunohistochemistry to characterize intraprostatic lymphocytes.Results: Prostatic epithelia constitutively produce IL-7 and, to a lesser extent, BAFF/BLyS. Indeed, we show that IL-7 receptor α is expressed by intraepithelial T lymphocytes and parafollicular T cells, whereas BAFF-R is found on periglandular B lymphocytes and mantle zone B cells of LFs. Prostate-homing B and T lymphocytes are scarcely proliferating, whereas most of them express the antiapoptotic protein bcl-2 and reveal a low apoptotic index in the terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay. The transition from normal to neoplastic glands in prostate cancer (PCa) is marked by a dramatic decline of IL-7 and BAFF/BLyS production. Accordingly, PCa is characterized by a significant reduction of intraepithelial lymphocytes and loss of LFs. B-cell and T-cell expression of bcl-2 decrease, whereas the apoptotic events increase. The remaining PCa-infiltrating lymphocytes are mostly CD8+ T cells that lack terminal differentiation and barely penetrate neoplastic glands.Conclusions: These results suggest that epithelial IL-7 and BAFF/BLyS production support intraprostatic lymphocyte survival. Its loss in PCa is associated with a severe depletion of prostate-associated lymphocytes and points to a novel tumor escape mechanism.
Prostate Cancer–Associated Gene Expression Alterations Determined from Needle Biopsies
Authors: Qian David Z. , Huang Chung-Ying , O'Brien Catherine A. , Coleman Ilsa M. , Garzotto Mark , True Lawrence D. , Higano Celestia S. , Vessella Robert , Lange Paul H. , Nelson Peter S. , Beer Tomasz M. 
Published: April 2009

Abstract
Purpose: To accurately identify gene expression alterations that differentiate neoplastic from normal prostate epithelium using an approach that avoids contamination by unwanted cellular components and is not compromised by acute gene expression changes associated with tumor devascularization and resulting ischemia.
Experimental Design: Approximately 3,000 neoplastic and benign prostate epithelial cells were isolated using laser capture microdissection from snap-frozen prostate biopsy specimens provided by 31 patients who subsequently participated in a clinical trial of preoperative chemotherapy. cDNA synthesized from amplified total RNA was hybridized to custom-made microarrays composed of 6,200 clones derived from the Prostate Expression Database. Expression differences for selected genes were verified using quantitative reverse transcription-PCR.
Results: Comparative analyses identified 954 transcript alterations associated with cancer (q &lt; 0.01%), including 149 differentially expressed genes with no known functional roles. Gene expression changes associated with ischemia and surgical removal of the prostate gland were absent. Genes up-regulated in prostate cancer were statistically enriched in categories related to cellular metabolism, energy use, signal transduction, and molecular transport. Genes down-regulated in prostate cancers were enriched in categories related to immune response, cellular responses to pathogens, and apoptosis. A heterogeneous pattern of androgen receptor expression changes was noted. In exploratory analyses, androgen receptor down-regulation was associated with a lower probability of cancer relapse after neoadjuvant chemotherapy followed by radical prostatectomy.
Conclusions: Assessments of tumor phenotypes based on gene expression for treatment stratification and drug targeting of oncogenic alterations may best be ascertained using biopsy-based analyses where the effects of ischemia do not complicate interpretation.
Supplementation with Branched-chain Amino Acids Inhibits Azoxymethane-induced Colonic Preneoplastic Lesions in Male C57BL/KsJ-db/db Mice
Authors: Shimizu Masahito , Shirakami Yohei , Iwasa Junpei , Shiraki Makoto , Yasuda Yoichi , Hata Kazuya , Hirose Yoshinobu , Tsurumi Hisashi , Tanaka Takuji , Moriwaki Hisataka 
Published: April 2009

Abstract
Purpose: Obesity and related metabolic abnormalities, including insulin resistance and activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis, are risk factors for colon cancer. Supplementation with branched-chain amino acids (BCAA) reduces the risk of liver cancer in cirrhotic patients who are obese, and this has been associated with an improvement of insulin resistance. The present study examined the effects of BCAA on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice that were obese and had hyperinsulinemia.
Experimental Design: Male db/db mice were given 4 weekly s.c. injections of AOM (15 mg/kg of body weight) and then they were fed a diet containing 3.0% BCAA or casein, a nitrogenc content–matched control diet, for 7 weeks.
Results: Feeding with BCAA caused a significant reduction in the number of total aberrant crypt foci and β-catenin accumulated crypts, both of which are premalignant lesions of the colon, compared with the control diet–fed groups. BCAA supplementation caused a marked decrease in the expression of IGF-IR, the phosphorylated form of IGF-IR, phosphorylated glycogen synthase kinase 3β, phosphorylated Akt, and cyclooxygenase-2 proteins on the colonic mucosa of AOM-treated mice. The serum levels of insulin, IGF-I, IGF-II, triglyceride, total cholesterol, and leptin were also decreased by supplementation with BCAA.
Conclusion: BCAA supplementation in diet improves insulin resistance and inhibits the activation of the IGF/IGF-IR axis, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model that was also associated with hyperlipidemia and hyperinsulinemia. BCAA, therefore, may be a useful chemoprevention modality for colon cancer in obese people.
A Potent, Imaging Adenoviral Vector Driven by the Cancer-selective Mucin-1 Promoter That Targets Breast Cancer Metastasis
Authors: Huyn Steven T. , Burton Jeremy B. , Sato Makoto , Carey Michael , Gambhir Sanjiv S. , Wu Lily 
Published: April 2009

Abstract
Purpose: With breast cancer, early detection and proper staging are critical, and will often influence both the treatment regimen and the therapeutic outcome for those affected with this disease. Improvements in these areas will play a profound role in reducing mortality from breast cancer.
Experimental Design: In this work we developed a breast cancer–targeted serotype 5 adenoviral vector, utilizing the tumor-specific mucin-1 promoter in combination with the two-step transcriptional amplification system, a system used to augment the activity of weak tissue–specific promoters.
Results: We showed the strong specificity of this tumor-selective adenovirus to express the luciferase optical imaging gene, leading to diagnostic signals that enabled detection of sentinel lymph node metastasis of breast cancer. Furthermore, we were able to target hepatic metastases following systemic administration of this mucin-1 selective virus.
Conclusions: Collectively, we showed that the amplified mucin-1 promoter–driven vector is able to deliver to and selectively express a desirable transgene in metastatic lesions of breast tumors. This work has strong clinical relevance to current diagnostic staging approaches, and could add to targeted therapeutic strategies to advance the fight against breast cancer.
Evaluation of 8q24 and 17q Risk Loci and Prostate Cancer Mortality
Authors: Penney Kathryn L. , Salinas Claudia A. , Pomerantz Mark , Schumacher Fredrick R. , Beckwith Christine A. , Lee Gwo-Shu , Oh William K. , Sartor Oliver , Ostrander Elaine A. , Kurth Tobias , Ma Jing , Mucci Lorelei , Stanford Janet L. , Kantoff Philip W. , Hunter David J. , Stampfer Meir J. , Freedman Matthew L. 
Published: April 2009

Abstract
Purpose: Variants at chromosomal loci 8q24 and 17q are established risk factors for prostate cancer. Many studies have confirmed the findings for risk, but few have examined aggressiveness and other clinical variables in detail. Additionally, Gleason score is typically used as a surrogate for the primary end point of prostate cancer mortality. We investigated whether the 8q24 and 17q risk variants are associated with clinical variables as well as prostate cancer mortality.
Experimental Design: In the Physicians' Health Study (1,347 cases and 1,462 controls), the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center; 3,714 cases), and the Fred Hutchinson Cancer Research Center King County Case-Control Studies (1,308 cases and 1,266 controls), we examined eight previously identified 8q24 and 17q risk variants for association with prostate cancer mortality in men of European ancestry. We considered associations with other surrogate markers of prostate cancer aggressiveness, such as Gleason score, pathologic stage, prostate-specific antigen at diagnosis, and age at diagnosis.
Results: Six of the eight variants were confirmed as prostate cancer risk factors. Several variants were nominally associated with age at diagnosis; when totaling all alleles for single nucleotide polymorphisms significantly associated with risk, each additional allele decreased age at diagnosis by an average of 6 months in the Physicians' Health Study (P = 0.0005) and 4 months in the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center) cohort (P = 0.0016). However, there were no statistically significant associations with prostate cancer mortality.
Conclusions: Our results suggest that the 8q24 and 17q prostate cancer risk variants may influence age at diagnosis but not disease aggressiveness.
Mutation-Specific Antibodies for the Detection of EGFR Mutations in Non–Small-Cell Lung Cancer
Authors: Yu Jian , Kane Susan , Wu Jiong , Benedettini Elisa , Li Daiqiang , Reeves Cynthia , Innocenti Gregory , Wetzel Randy , Crosby Katherine , Becker Alison , Ferrante Michelle , Cheung Wan Cheung , Hong Xiqiang , Chirieac Lucian R. , Sholl Lynette M. , Haack Herbert , Smith Bradley L. , Polakiewicz Roberto D. , Tan Yi , Gu Ting-Lei , Loda Massimo , Zhou Xinmin , Comb Michael J. 
Published: April 2009

Abstract
Purpose: Activating mutations within the tyrosine kinase domain of epidermal growth factor receptor (EGFR) are found in approximately 10% to 20% of non–small-cell lung cancer (NSCLC) patients and are associated with response to EGFR inhibitors. The most common NSCLC-associated EGFR mutations are deletions in exon 19 and L858R mutation in exon 21, together accounting for 90% of EGFR mutations. To develop a simple, sensitive, and reliable clinical assay for the identification of EGFR mutations in NSCLC patients, we generated mutation-specific rabbit monoclonal antibodies against each of these two most common EGFR mutations and aimed to evaluate the detection of EGFR mutations in NSCLC patients by immunohistochemistry.
Experimental Design: We tested mutation-specific antibodies by Western blot, immunofluorescence, and immunohistochemistry. In addition, we stained 40 EGFR genotyped NSCLC tumor samples by immunohistochemistry with these antibodies. Finally, with a panel of four antibodies, we screened a large set of NSCLC patient samples with unknown genotype and confirmed the immunohistochemistry results by DNA sequencing.
Results: These two antibodies specifically detect the corresponding mutant form of EGFR by Western blotting, immunofluorescence, and immunohistochemistry. Screening a panel of 340 paraffin-embedded NSCLC tumor samples with these antibodies showed that the sensitivity of the immunohistochemistry assay is 92%, with a specificity of 99% as compared with direct and mass spectrometry–based DNA sequencing.
Conclusions: This simple assay for detection of EGFR mutations in diagnostic human tissues provides a rapid, sensitive, specific, and cost-effective method to identify lung cancer patients responsive to EGFR-based therapies.
In vitro and In vivo Radiosensitization with AZD6244 (ARRY-142886), an Inhibitor of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase 1/2 Kinase
Authors: Chung Eun Joo , Brown Aaron P. , Asano Hiroaki , Mandler Mariana , Burgan William E. , Carter Donna , Camphausen Kevin , Citrin Deborah 
Published: April 2009

Abstract
Purpose: The mitogen-activated protein (MAP) kinase pathway is important for cell proliferation, survival, and differentiation, and is frequently up-regulated in cancers. The MAP kinase pathway is also activated after exposure to ionizing radiation. We investigated the effects of AZD6244 (ARRY-142886), an inhibitor of MAP kinase/extracellular signal-regulated kinase 1/2, on radiation response.
Experimental Design: The effects of AZD6244 on the in vitro radiosensitivity of human cancer cell lines (A549, MiaPaCa2, and DU145) were evaluated using clonogenic assays. DNA damage repair was evaluated using γH2AX, and mitotic catastrophe was measured using nuclear fragmentation. Cell cycle effects were measured with flow cytometry. Growth delay was used to evaluate the effects of AZD6244 on in vivo tumor radiosensitivity.
Results: Exposure of each cell line to AZD6244 before irradiation resulted in an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1, ranging from 1.16 to 2.0. No effects of AZD6244 on radiation-induced apoptosis or persistence of γH2AX foci after irradiation were detected. Cells treated with AZD6244 had an increased mitotic index and decreased Chk1 phosphorylation at 1 and 2 hours after irradiation. Mitotic catastrophe was increased in cells receiving AZD6244 and irradiation compared with the single treatments. In vivo studies revealed that AZD6244 administration to mice bearing A549 tumor xenografts resulted in a greater than additive increase in radiation-induced tumor growth delay (dose enhancement factor of 3.38).
Conclusions: These results indicate that AZD6244 can enhance tumor cell radiosensitivity in vitro and in vivo and suggest that this effect involves an increase in mitotic catastrophe.