bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Mitochondrial Uncoupling Protein-2 Promotes Chemoresistance in Cancer Cells
Authors: Derdak Zoltan , Mark Nicholas M. , Beldi Guido , Robson Simon C. , Wands Jack R. , Baffy György 
Published: April 2008

Abstract
Cancer cells acquire drug resistance as a result of selection pressure dictated by unfavorable microenvironments. This survival process is facilitated through efficient control of oxidative stress originating from mitochondria that typically initiates programmed cell death. We show this critical adaptive response in cancer cells to be linked to uncoupling protein-2 (UCP2), a mitochondrial suppressor of reactive oxygen species (ROS). UCP2 is present in drug-resistant lines of various cancer cells and in human colon cancer. Overexpression of UCP2 in HCT116 human colon cancer cells inhibits ROS accumulation and apoptosis after exposure to chemotherapeutic agents. Tumor xenografts of UCP2-overexpressing HCT116 cells retain growth in nude mice receiving chemotherapy. Augmented cancer cell survival is accompanied by altered NH2-terminal phosphorylation of the pivotal tumor suppressor p53 and induction of the glycolytic phenotype (Warburg effect). These findings link UCP2 with molecular mechanisms of chemoresistance. Targeting UCP2 may be considered a novel treatment strategy for cancer. [Cancer Res 2008;68(8):2813–9]
Breast Carcinoma–Associated Fibroblasts and Their Counterparts Display Neoplastic-Specific Changes
Authors: Hawsawi Nahed M. , Ghebeh Hazem , Hendrayani Siti-Faujiah , Tulbah Asma , Al-Eid Maha , Al-Tweigeri Taher , Ajarim Dahish , Alaiya Ayodele , Dermime Said , Aboussekhra Abdelilah 
Published: April 2008

Abstract
It has become clear that the initiation and progression of carcinomas depend not only on alterations in epithelial cells, but also on changes in their microenvironment. To identify these changes, we have undertaken cellular and molecular characterization of carcinoma-associated fibroblasts (CAF) and their tumor counterpart fibroblasts (TCF) isolated from 12 breast cancer patients. Normal breast fibroblasts (NBF) from plastic surgery were used as normal control. We present evidence that both CAFs and TCFs are myofibroblasts and show tumor-associated features. Indeed, the p53/p21 response pathway to γ-rays was defective in 70% CAFs, whereas it was normal in all the TCF and NBF cells. In addition, the basal levels of the p53 and p21 proteins were significantly low in 83% of CAFs and modulated in the majority of TCFs compared with NBFs. Interestingly, both TCFs and CAFs expressed high levels of the cancer marker survivin and consequently exhibited high resistance to cisplatin and UV light. Moreover, most CAFs were positive for the proliferation marker Ki-67 and exhibited high proliferation rate compared with NBFs and TCFs. However, proliferating cell nuclear antigen was highly expressed in both CAFs and TCFs. Using the two-dimensional gel electrophoresis technique, we have also shown that CAF, TCF, and NBF cells present different proteome profiles, with many proteins differentially expressed between these cells. Taken together these results indicate that different genetic alterations can occur in breast CAFs and their corresponding adjacent counterparts, showing the important role that stroma could play in breast carcinogenesis and treatment. [Cancer Res 2008;68(8):2717–25]
Identification of Let-7–Regulated Oncofetal Genes
Authors: Boyerinas Benjamin , Park Sun-Mi , Shomron Noam , Hedegaard Mads M. , Vinther Jeppe , Andersen Jens S. , Feig Christine , Xu Jinbo , Burge Christopher B. , Peter Marcus E. 
Published: April 2008

Abstract
MicroRNAs (miRNA) are small RNA molecules of ∼20 to 22 nucleotides that reduce expression of proteins through mRNA degradation and/or translational silencing. Each known miRNA has a large number of predicted targets. Members of the let-7/miR-98 family of miRNAs are up-regulated at the end of embryonic development. Let-7 is often down-regulated early during cancer development, suggesting that let-7–regulated oncofetal genes (LOG) may become reexpressed in cancer cells. Using comparative bioinformatics, we have identified 12 conserved LOGs that include HMGA2 and IMP-1/CRD-BP. IMP-1 has growth-promoting activities through stabilization of c-myc mRNA. We experimentally confirmed that IMP-1 is a direct let-7 target that promotes cell growth and motility of tumor cells, and we confirmed by proteomics analysis that IMP-1 and HMGA2 are major miRNA targets. Our data suggest that a substantial part of the growth inhibitory activities of let-7 comes from suppressing the expression of IMP-1. LOGs could be novel therapeutic targets and potential biomarkers for cancer treatment. [Cancer Res 2008;68(8):2587–91]
A Phase I Biological Study of MG98, an Oligodeoxynucleotide Antisense to DNA Methyltransferase 1, in Patients with High-Risk Myelodysplasia and Acute Myeloid Leukemia
Authors: Klisovic Rebecca B. , Stock Wendy , Cataland Spero , Klisovic Marko I. , Liu Shujun , Blum William , Green Margaret , Odenike Olatoyosi , Godley Lucy , Burgt Jennifer Vanden , Van Laar Emily , Cullen Michael , Macleod A. Robert , Besterman Jeffrey M. , Reid Gregory K. , Byrd John C. , Marcucci Guido 
Published: April 2008

AbstractPurpose: Epigenetic silencing via aberrant promoter DNA hypermethylation of normal genes has been described as a leukemogenic mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We hypothesized that MG98, an oligonucleotide antisense to DNA methyltransferase 1 (DNMT1), could reverse malignant phenotypes by down-regulating DNMT1 and inducing reexpression of hypermethylated genes. This phase I study was conducted to determine a biologically effective dose and describe the safety of MG98 in MDS/AML.Experimental Design: Twenty-three patients with MDS (n = 11) and AML (n = 12) were enrolled. Biologically effective dose was defined as the dose at which ≥50% of patients experienced &gt;50% reduction in DNMT1 expression with acceptable toxicity. Escalating doses of MG98 were administered according to two schedules (2-hour i.v. bolus followed by 5-day continuous i.v. infusion every 14 days, or 14-day continuous i.v. infusion every 21 days).Results: DNMT1 down-regulation was observed in 8 patients. However, biologically effective dose was not reached. Reexpression of target genes (P15, WIT1, and ER) was observed in 12 patients but did not correlate with DNMT1 down-regulation. Escalation was stopped due to dose-limiting toxicities (bone pain, nausea, and fever). No objective clinical response was observed. Disease stabilization occurred in 6 (26%) patients.Conclusions: No pharmacodynamic or clinical activity was observed at MG98 doses and schedules administered. Despite this, pursuing DNMT1 down-regulation remains a sound approach for targeting aberrant epigenetics in AML/MDS. Future studies with different formulation and/or doses and schedules will be required to ensure efficient MG98 intracellular uptake and fully evaluate its therapeutic potential.
The Use of Magnetic Resonance Imaging to Noninvasively Detect Genetic Signatures in Oligodendroglioma
Authors: Brown Robert , Zlatescu Magdalena , Sijben Angelique , Roldan Gloria , Easaw Jay , Forsyth Peter , Parney Ian , Sevick Robert , Yan Elizabeth , Demetrick Douglas , Schiff David , Cairncross Gregory , Mitchell Ross 
Published: April 2008

Abstract
Background: Some patients with low-grade glioma have extraordinarily long survival times; current, early treatment does not prolong their lives. For this reason, therapies that sometimes have neurologic side effects are often deferred intentionally.
Methods: In a study of oligodendrogliomas, we used a quantitative method of MR analysis based on the S-transform to investigate whether codeletion of chromosomes 1p and 19q, a marker of good prognosis, could be predicted accurately by measuring image texture.
Results: Differences in texture were seen between tumors with codeletion of chromosomes 1p and 19q and those with intact 1p and 19q alleles on contrast-enhanced T1-weighted and T2-weighted MR images. Quantitative MR texture on T2 images predicted codeletion of chromosomes 1p and 19q with high sensitivity and specificity.
Conclusions: This new method of MR image interpretation may have the potential to augment the diagnostic assessment of patients with suspected low-grade glioma.
Randomized, Double-Blinded Phase II Evaluation of Docetaxel with or without Doxercalciferol in Patients with Metastatic, Androgen-Independent Prostate Cancer
Authors: Attia Steven , Eickhoff Jens , Wilding George , McNeel Douglas , Blank Jules , Ahuja Harish , Jumonville Alcee , Eastman Michael , Shevrin Daniel , Glode Michael , Alberti Dona , Staab Mary Jane , Horvath Dottie , Straus Jane , Marnocha Rebecca , Liu Glenn 
Published: April 2008

Abstract
Purpose: Docetaxel is standard of care for androgen-independent prostate cancer (AIPC). Doxercalciferol (1α-hydroxyvitamin D2) had modest activity in phase I/II trials. Preclinical data support combining vitamin D analogues with docetaxel to treat AIPC.
Experimental Design: Chemotherapy-naive men with metastatic AIPC were randomized 1:1 to receive, on a 4-week cycle, docetaxel (35 mg/m2 i.v., days 1, 8, and 15) with or without doxercalciferol (10 μg orally, days 1-28). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were progression-free survival, overall survival, objective response, and toxicity. Survival was analyzed as intent to treat.
Results: Seventy patients were randomized. Median follow-up was 17.6 months (range, 3.3-45.2). PSA response rate was 46.7% [95% confidence interval (95% CI), 30-64] in the doxercalciferol arm and 39.4% (95% CI, 25-56) with placebo (P = 0.560). Median progression-free survival in the doxercalciferol arm was 6.17 months (95% CI, 4.20-10.7) versus 6.20 months (95% CI, 4.83-9.07) with placebo (P = 0.764). Median overall survival in the doxercalciferol arm was 17.8 months (95% CI, 14.9-23.6) versus 16.4 months (95% CI, 11.9-23.8) with placebo (P = 0.383). Twenty-four patients in the doxercalciferol arm and 23 in the placebo arm were evaluable for objective response. No complete responses were observed. Partial objective response rate was 12.5% with doxercalciferol versus 8.7% with placebo (P = 0.672). Rate of grade ≥3 toxicity was 46% with doxercalciferol versus 42% with placebo (P = 0.785).
Conclusions: Daily doxercalciferol with weekly docetaxel did not enhance PSA response rate or survival. Toxicity was similar between arms. Despite the disappointing results of this study, other vitamin D analogues remain under active investigation.
EXEL-7647 Inhibits Mutant Forms of ErbB2 Associated with Lapatinib Resistance and Neoplastic Transformation
Authors: Trowe Torsten , Boukouvala Sotiria , Calkins Keith , Cutler Richard E. , Fong Ryan , Funke Roel , Gendreau Steven B. , Kim Yong D. , Miller Nicole , Woolfrey John R. , Vysotskaia Valentina , Yang Jing Ping , Gerritsen Mary E. , Matthews David J. , Lamb Peter , Heuer Timothy S. 
Published: April 2008

Abstract
Purpose: Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss of clinical efficacy for kinase-targeted therapeutics. We report the prospective discovery of ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib.
Experimental Design: We did in vitro screening using a randomly mutagenized ErbB2 expression library in Ba/F3 cells, which were dependent on ErbB2 activity for survival and growth.
Results: Lapatinib resistance screens identified mutations at 16 different ErbB2 amino acid residues, with 12 mutated amino acids mapping to the kinase domain. Mutations conferring the greatest lapatinib resistance cluster in the NH2-terminal kinase lobe and hinge region. Structural computer modeling studies suggest that lapatinib resistance is caused by multiple mechanisms; including direct steric interference and restriction of conformational flexibility (the inactive state required for lapatinib binding is energetically unfavorable). ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptor T790M, ABL T315I, and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance. ErbB2 mutants associated with lapatinib resistance transformed NIH-3T3 cells, including L755S and T733I mutations known to occur in human breast and gastric carcinomas, supporting a direct mechanism for lapatinib resistance in ErbB2-driven human cancers. The epidermal growth factor receptor/ErbB2/vascular endothelial growth factor receptor inhibitor EXEL-7647 was found to inhibit almost all lapatinib resistance-associated mutations. Furthermore, no ErbB2 mutations were found to be associated with EXEL-7647 resistance and lapatinib sensitivity.
Conclusions: Taken together, these data suggest potential target-based mechanisms of resistance to lapatinib and suggest that EXEL-7647 may be able to circumvent these effects.
A Genotype-Phenotype Examination of Cyclin D1 on Risk and Outcome of Squamous Cell Carcinoma of the Head and Neck
Authors: Marsit Carmen J. , Black Candice C. , Posner Marshall R. , Kelsey Karl T. 
Published: April 2008

Abstract
Purpose: The variant allele of CCND1 G870A encodes a splice variant of the cyclin D1 protein, which possesses an increased half-life. To confirm the phenotypic effect of the variant allele, we examined the immunohistochemical staining pattern of the protein in tumors from a case population of head and neck squamous cell carcinoma (HNSCC) and compared it with the genotype of these individuals. We also examined how this genotype was associated with the risk of HNSCC and if this genotype-phenotype association was related to patient outcome.
Experimental Design: In a population-based case-control study of 698 cases and 777 controls, we both genotyped all participants for the CCND1 gene and did immunohistochemical staining of the cyclin D1 protein in the HNSCC tumors.
Results: The variant AA genotype was significantly associated with positive immunohistochemical staining (P &lt; 0.02), and this variant genotype was associated with a significantly elevated odds ratio of 1.5 (95% confidence interval, 1.1-2.0) for HNSCC overall, with risk greatest in oral and laryngeal sites. Positive immunohistochemical staining was inversely related to human papillomavirus 16 DNA present in the tumor (P &lt; 0.03). The AA genotype and superpositive immunohistochemical staining for cyclin D1 also had independent and significant effects on patient survival.
Conclusions: These results strongly suggest that this splice variant, when present in two copies, is a significant predictor of both the occurrence of HNSCC as well as patient survival after treatment. These data further indicate that this variant protein is an important determinant of individual response to therapy for this disease.
Amphiregulin Is a Promising Prognostic Marker for Liver Metastases of Colorectal Cancer
Authors: Yamada Michiyo , Ichikawa Yasushi , Yamagishi Shigeru , Momiyama Nobuyoshi , Ota Mitsuyoshi , Fujii Syoichi , Tanaka Kuniya , Togo Shinji , Ohki Shigeo , Shimada Hiroshi 
Published: April 2008

Abstract
Purpose: Aberrant activation of epidermal growth factor receptors (EGFR/HER1) by ligand stimulation or heterodimerization with human epidermal growth factor 2 (HER2) is considered to play an important role in the development of colorectal carcinoma. Amphiregulin (AR) is a ligand of EGFR that might be related to the development and progression of gastrointestinal tumors. The aim of this study was to determine the AR, EGFR, and HER2 protein expression levels and to evaluate their prognostic relevance to the clinical course of colorectal cancer.
Experimental Design: The AR, EGFR, and HER2 protein levels in primary tumors of colorectal cancer (n = 106) were examined using immunohistochemistry. Metastatic sites in liver specimens (n = 16) were also analyzed in the same manner.
Results: Thirteen (81.6%) metastatic lesions of the liver stained positive for AR. Among the primary lesions of colorectal cancer, 58 (54.7%) stained positive for AR, 13 (12.3%) stained positive for EGFR, and 5 (4.7%) stained positive for HER2. When the relationships between each protein expression level and the clinicopathologic factors were examined, only the AR expression level was significantly related to liver metastasis (P = 0.0296). A multivariate analysis of liver metastasis proved that AR expression was an independent prognostic factor of liver metastasis from colorectal cancer (P = 0.0217).
Conclusions: AR expression in primary lesions of colorectal cancer is an important predictive marker of liver metastasis.
Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma
Authors: Chen Jack S. , Zhou Linda J. , Entin-Meer Michal , Yang Xiaodong , Donker Mila , Knight Zachary A. , Weiss William , Shokat Kevan M. , Haas-Kogan Daphne , Stokoe David 
Published: April 2008

Abstract
The phosphoinositide 3′-kinase (PI3K)–mediated signaling pathway plays a key role in fundamental cellular functions important in normal cellular homeostasis and malignant transformation. Deregulated signaling through this pathway contributes to development of gliomas and their resistance to radiation and chemotherapy. Targeting the PI3K signaling pathway has thus emerged as a promising approach to successful treatment of gliomas. We assessed the radiosensitizing potential of four small-molecule inhibitors that differ in their activities against specific isoforms of the PI3K 110-kDa catalytic subunit (p110). p110α inhibitors blocked phosphorylation of both protein kinase B/Akt and S6 in all cell lines examined, effectively decreased cellular proliferation, and produced additive cytotoxic effects in combination with radiation therapy. The p110β inhibitor exhibited limited biochemical effects and failed to decrease cellular proliferation or viability as either a single agent or in combination with radiation or rapamycin. In vivo studies examining the effects of the p110α inhibitor in combination with radiation indicated a significant reduction in tumor growth rate induced by the combined treatment compared with each treatment modality alone. This translated into a trend toward prolonged time-to-failure for mice in the combination treatment group. In conclusion, PI3K inhibitors are promising agents in the treatment of glioblastomas, especially when used in combination with ionizing radiation. [Mol Cancer Ther 2008;7(4):841–50]
Histone deacetylase inhibitor FK228 enhances adenovirus-mediated p53 family gene therapy in cancer models
Authors: Sasaki Yasushi , Negishi Hideaki , Idogawa Masashi , Suzuki Hiromu , Mita Hiroaki , Toyota Minoru , Shinomura Yasuhisa , Imai Kohzoh , Tokino Takashi 
Published: April 2008

Abstract
Therapeutic replacement of the wild-type p53 gene has been pursued as a potential gene therapy strategy in a variety of cancer types; however, some cancer models are resistant to p53 in vivo and in vitro. Therefore, to improve p53 gene therapy, it is important to overcome the resistance to p53-mediated apoptosis. Histone deacetylase inhibitors are a novel class of chemotherapeutic agents that are able to reverse the malignant phenotype of transformed cells. A natural histone deacetylase inhibitor, FK228, is reported to enhance adenovirus infection due in part to the up-regulation of coxsackievirus adenovirus receptor expression. In this study, preclinical experiments were done to establish a mechanistic rationale for the combination of adenovirus-mediated p53 family gene transfer and FK228 pretreatment in future clinical trials. Pretreatment with FK228 enhanced apoptosis in human cancer cells through enhanced transduction of Ad-p53. FK228 also induced hyperacetylation of the p53 protein and specifically enhanced p53-mediated Noxa expression. Additionally, the combination of FK228 and Ad-p53 induced Bax translocation to the mitochondria. The double knockdown of Bax and Noxa expression by small interfering RNA antagonized the synergistic effect of Ad-p53 and FK228 on apoptosis induction. In human cancer xenograft models, FK228 significantly increased the therapeutic effectiveness of p53 as well as p63 gene therapy. These results provide a strong rationale for combining p53 gene therapy and FK228 pretreatment in cancer therapy. [Mol Cancer Ther 2008;7(4):779–87]
Pharmacologic properties of AG-012986, a pan-cyclin-dependent kinase inhibitor with antitumor efficacy
Authors: Zhang Cathy , Lundgren Karen , Yan Zhengming , Arango Maria E. , Price Sharon , Huber Andrea , Higgins Joseph , Troche Gabriel , Skaptason Judith , Koudriakova Tatiana , Nonomiya Jim , Yang Michelle , O'Connor Patrick , Bender Steve , Los Gerrit , Lewis Cristina , Jessen Bart 
Published: April 2008

AbstractAG-012986 is a multitargeted cyclin-dependent kinase (CDK) inhibitor active against CDK1, CDK2, CDK4/6, CDK5, and CDK9, with selectivity over a diverse panel of non-CDK kinases. Here, we report the potent antitumor efficacies of AG-012986 against multiple tumor lines in vitro and in vivo. AG-012986 showed antiproliferative activities in vitro with IC50s of &lt;100 nmol/L in 14 of 18 tumor cell lines. In vivo, significant antitumor efficacy induced by AG-012986 was seen (tumor growth inhibition, &gt;83.1%) in 10 of 11 human xenograft tumor models when administered at or near the maximum tolerated dose for 8 or 12 days. AG-012986 caused dose-dependent hypophosphorylation at Ser795 of the retinoblastoma protein, cell cycle arrest, and apoptosis in vitro. Colony-forming assays indicated that the potency of AG-012986 substantially decreased with treatment time of &lt;24 h. In vivo, AG-012986 also showed dose-dependent retinoblastoma Ser795 hypophosphorylation, cell cycle arrest, decreased Ki-67 tumor staining, and apoptosis in conjunction with antitumor activity. Studies comparing i.p. bolus with s.c. implanted minipump dosing regimens revealed that in vivo efficacy correlated with the duration of minimally effective plasma levels rather than maximal drug plasma levels. Dosing optimization of AG-012986 provided guidance for selecting a treatment schedule to achieve the best antitumor efficacy while minimizing the risk of adverse side effects. [Mol Cancer Ther 2008;7(4):818–28]
Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells
Authors: Ambrosini Grazia , Cheema Haider S. , Seelman Sharon , Teed Allison , Sambol Elliot B. , Singer Samuel , Schwartz Gary K. 
Published: April 2008

Abstract
Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue tumors with a very poor prognosis and largely resistant to chemotherapy. MPNSTs are characterized by activation of the Ras pathway by loss of tumor suppressor neurofibromatosis type 1. In view of this, MPNST may be susceptible to inhibition of the activated Ras/Raf/mitogen-activated protein kinase pathway by the B-Raf inhibitor sorafenib. MPNST (MPNST and ST8814) and dedifferentiated liposarcoma (LS141 and DDLS) human tumor cell lines were characterized for Ras activation and B-Raf expression. Tumor cells were treated with sorafenib and examined for growth inhibition, inhibition of phospho-MEK, phospho-ERK, cell cycle arrest, and changes in cyclin D1 and pRb expression. MPNSTs were sensitive to sorafenib at nanomolar concentrations. This appeared to be due to inhibition of phospho-MEK, phospho-ERK, suppression of cyclin D1, and hypophosphorylation of pRb at the CDK4-specific sites, resulting in a G1 cell cycle arrest. These effects were not seen in the liposarcoma cells, which either did not express B-Raf or showed decreased Ras activation. Small interfering RNA–mediated depletion of B-Raf in MPNSTs also induced a G1 cell cycle arrest in these cells, with a marked inhibition of cyclin D1 expression and Rb phosphorylation, whereas depletion of C-Raf did not affect either. With growth inhibition at the low nanomolar range, sorafenib, by inhibiting the mitogen-activated protein kinase pathway, may prove to be a novel therapy for patients with MPNST. [Mol Cancer Ther 2008;7(4):890–6]