bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Inhibition of BRCA2-Deficient Mammary Tumor Cell Growth by AZD2281 and Cisplatin
Authors: Evers Bastiaan , Drost Rinske , Schut Eva , de Bruin Michiel , van der Burg Eline , Derksen Patrick W.B. , Holstege Henne , Liu Xiaoling , van Drunen Ellen , Beverloo H. Berna , Smith Graeme C.M. , Martin Niall M.B. , Lau Alan , O'Connor Mark J. , Jonkers Jos 
Published: June 2008

Abstract
Purpose: To assess efficacy of the novel, selective poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor AZD2281 against newly established BRCA2-deficient mouse mammary tumor cell lines and to determine potential synergy between AZD2281 and cisplatin.
Experimental Design: We established and thoroughly characterized a panel of clonal cell lines from independent BRCA2-deficient mouse mammary tumors and BRCA2-proficient control tumors. Subsequently, we assessed sensitivity of these lines to conventional cytotoxic drugs and the novel PARP inhibitor AZD2281. Finally, in vitro combination studies were done to investigate interaction between AZD2281 and cisplatin.
Results: Genetic, transcriptional, and functional analyses confirmed the successful isolation of BRCA2-deficient and BRCA2-proficient mouse mammary tumor cell lines. Treatment of these cell lines with 11 different anticancer drugs or with γ-irradiation showed that AZD2281, a novel and specific PARP inhibitor, caused the strongest differential growth inhibition of BRCA2-deficient versus BRCA2-proficient mammary tumor cells. Finally, drug combination studies showed synergistic cytotoxicity of AZD2281 and cisplatin against BRCA2-deficient cells but not against BRCA2-proficient control cells.
Conclusion: We have successfully established the first set of BRCA2-deficient mammary tumor cell lines, which form an important addition to the existing preclinical models for BRCA-mutated breast cancer. The exquisite sensitivity of these cells to the PARP inhibitor AZD2281, alone or in combination with cisplatin, provides strong support for AZD2281 as a novel targeted therapeutic against BRCA-deficient cancers.
Imaging Immune Response In vivo: Cytolytic Action of Genetically Altered T Cells Directed to Glioblastoma Multiforme
Authors: Lazovic Jelena , Jensen Michael C. , Ferkassian Evette , Aguilar Brenda , Raubitschek Andrew , Jacobs Russell E. 
Published: June 2008

Abstract
Purpose: Clinical trials have commenced to evaluate the feasibility of targeting malignant gliomas with genetically engineered CTLs delivered directly to the tumor bed in the central nervous system. The objective of this study is to determine a suite of magnetic resonance imaging (MRI) measurements using an orthotopic xenograft murine model that can noninvasively monitor immunologically mediated tumor regression and reactive changes in the surrounding brain parenchyma.
Experimental Design: Our preclinical therapeutic platform is based on CTL genetic modification to express a membrane tethered interleukin-13 (IL-13) cytokine chimeric T-cell antigen receptor. This enables selective binding and signal transduction on encountering the glioma-restricted IL-13 α2 receptor (IL-13Rα2). We used MRI to visualize immune responses following adoptive transfer of IL-13Rα2-specific CD8+ CTL clones.
Results: Based on MRI measurements, several phases following IL-13Rα2-specific T-cell adoptive transfer could be distinguished, all of which correlated well with glioblastoma regression confirmed on histology. The first detectable changes, 24 hours post-treatment, were significantly increased T2 relaxation times and strongly enhanced signal on T1-weighted postcontrast images. In the next phase, the apparent diffusion coefficient was significantly increased at 2 and 3 days post-treatment. In the last phase, at day 3 after IL-13Rα2-specific T-cell injection, the volume of hyperintense signal on T1-weighted postcontrast image was significantly decreased, whereas apparent diffusion coefficient remained elevated.
Conclusions: The present study indicates the feasibility of MRI to visualize different phases of immune response when IL-13Rα2-specific CTLs are administered directly to the glioma tumor bed. This will further the aim of better predicting clinical outcome following immunotherapy.
RHAMM, p21 Combined Phenotype Identifies Microsatellite Instability-High Colorectal Cancers with a Highly Adverse Prognosis
Authors: Zlobec Inti , Baker Kristi , Terracciano Luigi M. , Lugli Alessandro 
Published: June 2008

Abstract
Purpose: The aim of this study was to identify prognostic subgroups of microsatellite instability-high (MSI-H) colorectal cancers by combined analysis of 10 well-established immunohistochemical tumor markers and 7 clinicopathologic features.
Experimental Design: Using a tissue microarray, immunohistochemistry was done on 223 cases of MSI-H cancers for the following protein markers: raf-1 kinase inhibitor protein, receptor for hyaluronic acid–mediated motility, apoptosis protease activating factor-1, mammalian sterile20-like kinase 1, p21, p27, p53, ephrin B2 receptor, Ki-67, and epidermal growth factor receptor. Seven clinicopathologic features and all tumor markers were evaluated in univariate and multivariable analyses.
Results: RHAMM overexpression [P &lt; 0.001; hazard ratio [HR; 95% confidence interval (95% CI)], 3.86 (2.19-6.81)], loss of p21 [P = 0.002; 0.33 (0.16-0.67)], and higher N stage [P &lt; 0.001; 3.31 (1.9-5.8)] were independent adverse prognostic factors. RHAMM/p21 combinations were evaluated by N stage. Significant differences in survival were observed with various RHAMM/p21 combinations (P &lt; 0.001). Both node-negative and node-positive patients with RHAMM− tumors survived more than 120 months. Node-positive RHAMM+ patients had a strikingly worse prognosis [16.0 (10.0-63.0) months] and could further be divided into p21− patients [14.0 (9.0-27.0) months] and p21+ patients surviving 47.0 months. RHAMM+/p21− node-negative patients had a significantly shorter survival time than RHAMM+/p21+ tumors (P = 0.021).
Conclusion: These results suggest that the combined phenotype of RHAMM and p21 expression is an invaluable independent prognostic immunohistochemical profile in MSI-H colorectal cancer. Based on the prognostic subgroups identified in our cohort, node-negative patients overexpressing RHAMM but with loss of p21 may derive a potential benefit from postoperative treatment, whereas adjuvant chemotherapy should be reconsidered for MSI-H node-positive RHAMM− tumors.
A Metastasis Modifier Locus on Human Chromosome 8p in Uveal Melanoma Identified by Integrative Genomic Analysis
Authors: Onken Michael D. , Worley Lori A. , Harbour J. William 
Published: June 2008

Abstract
Purpose: To identify genes that modify metastatic risk in uveal melanoma, a type of cancer that is valuable for studying metastasis because of its remarkably consistent metastatic pattern and well-characterized gene expression signature associated with metastasis.
Experimental Design: We analyzed 53 primary uveal melanomas by gene expression profiling, array-based comparative genomic hybridization, array-based global DNA methylation profiling, and single nucleotide polymorphism–based detection of loss of heterozygosity to identify modifiers of metastatic risk. A candidate gene, leucine zipper tumor suppressor-1 (LZTS1), was examined for its effect on proliferation, migration, and motility in cultured uveal melanoma cells.
Results: In metastasizing primary uveal melanomas, deletion of chromosome 8p12-22 and DNA hypermethylation of the corresponding region of the retained hemizygous 8p allele were associated with more rapid metastasis. Among the 11 genes located within the deleted region, LZTS1 was most strongly linked to rapid metastasis. LZTS1 was silenced in rapidly metastasizing and metastatic uveal melanomas but not in slowly metastasizing and nonmetastasizing uveal melanomas. Forced expression of LZTS1 in metastasizing uveal melanoma cells inhibited their motility and invasion, whereas depletion of LZTS1 increased their motility.
Conclusions: We have described a metastatic modifier locus on chromosome 8p and identified LZTS1 as a potential metastasis suppressor within this region. This study shows the utility of integrative genomic methods for identifying modifiers of metastatic risk in human cancers and may suggest new therapeutic targets in metastasizing tumor cells.
RCAS/SCL-TVA Animal Model Allows Targeted Delivery of Polyoma Middle T Oncogene to Vascular Endothelial Progenitors In vivo and Results in Hemangioma Development
Authors: Sausville Justin , Molinolo Alfredo A. , Cheng Xiangfei , Frampton Jon , Takebe Naoko , Gutkind J. Silvio , Feldman Ricardo A. 
Published: June 2008

Abstract
Purpose: To recapitulate the generation of cancer stem cells in the context of an intact animal using a retroviral vector capable of in vivo delivery of oncogenes to primitive endothelial and hematopoietic stem cells.
Experimental Design: Targeting of these progenitors was achieved using transgenic mice in which the avian TVA retroviral receptor was placed under the control of the stem cell leukemia (scl/tal-1) gene promoter and SCL +19 enhancer.
Results: Injection of an avian retrovirus encoding polyoma middle T (PyMT), an oncogene that transforms endothelial cells, caused rapid lethality in all SCL-TVA mice but not in control TVA(−) littermates. The infected animals exhibited hemorrhagic foci in several organs. Histopathologic analysis confirmed the presence of hemangiomas and the endothelial origin of the PyMT-transformed cells. Surprisingly, the transformed endothelial cells contained readily detectable numbers of TVA(+) cells. By contrast, normal blood vessels had very few of these cells. The presence of TVA(+) cells in the lesions suggests that the cells originally infected by PyMT retained stem cell characteristics. Further analysis showed that the tumor cells exhibited activation of the phosphatidylinositol 3-kinase/Akt and S6/mammalian target of rapamycin pathways, suggesting a mechanism used by PyMT to transform endothelial progenitors in vivo.
Conclusions: We conclude that this experimental system can specifically deliver oncogenes to vascular endothelial progenitors in vivo and cause a fatal neoplastic disease. This animal model should allow the generation of endothelial cancer stem cells in the natural environment of an immunocompetent animal, thereby enabling the recapitulation of genetic alterations that are responsible for the initiation and progression of human malignancies of endothelial origin.
DNA-Dependent Protein Kinase Is a Therapeutic Target and an Indicator of Poor Prognosis in B-Cell Chronic Lymphocytic Leukemia
Authors: Willmore Elaine , Elliott Sarah L. , Mainou-Fowler Tryfonia , Summerfield Geoffrey P. , Jackson Graham H. , O'Neill Fran , Lowe Christopher , Carter Anthony , Harris Robert , Pettitt Andrew R. , Cano-Soumillac Celine , Griffin Roger J. , Cowell Ian G. , Austin Caroline A. , Durkacz Barbara W. 
Published: June 2008

Abstract
Purpose: del(17p), del(11q), and associated p53 dysfunction predict for short survival and chemoresistance in B-cell chronic lymphocytic leukemia (CLL). DNA-dependent protein kinase (DNA-PK) is activated by DNA damage and mediates DNA double-strand break repair. We hypothesized that inhibiting DNA-PK would sensitize CLL cells to drug-induced DNA damage and that this approach could increase the therapeutic index of agents used to treat CLL.
Experimental Design: Fifty-four CLL cases were characterized for poor prognosis markers [del(17p), del(11q), CD38, and ZAP-70]. In selected cases, DNA-PK catalytic subunit (DNA-PKcs) expression and activity and p53 function were also measured. Ex vivo viability assays established sensitivity to fludarabine and chlorambucil and also tested the ability of a novel DNA-PK inhibitor (NU7441) to sensitize CLL cells to these drugs. The effects of NU7441 on fludarabine-induced DNA damage repair were also assessed (Comet assays and detection of γH2AX).
Results: DNA-PKcs levels correlated with DNA-PK activity and varied 50-fold between cases but were consistently higher in del(17p) (P = 0.01) and del(11q) cases. NU7441 sensitized CLL cells to chlorambucil and fludarabine, including cases with del(17p), del(11q), p53 dysfunction, or high levels of DNA-PKcs. NU7441 increased fludarabine-induced double-strand breaks and abrogated drug-induced autophosphorylation of DNA-PKcs at Ser2056. High DNA-PK levels predicted for reduced treatment-free interval.
Conclusions: These data validate the concept of targeting DNA-PKcs in poor risk CLL, and demonstrate a mechanistic rationale for use of a DNA-PK inhibitor. The novel observation that DNA-PKcs is overexpressed in del(17p) and del(11q) cases indicates that DNA-PK may contribute to disease progression in CLL.
A Phase II Pharmacodynamic Study of Erlotinib in Patients with Advanced Non–Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy
Authors: Felip Enriqueta , Rojo Federico , Reck Martin , Heller Astrid , Klughammer Barbara , Sala Gemma , Cedres Susana , Peralta Sergio , Maacke Heiko , Foernzler Dorothee , Parera Marta , Möcks Joachim , Saura Cristina , Gatzemeier Ulrich , Baselga José 
Published: June 2008

Abstract
Purpose: To examine potential markers of clinical benefit and the effects of erlotinib on the epidermal growth factor receptor (EGFR) signaling pathway in advanced non–small cell lung cancer patients refractory to platinum-based chemotherapy.
Experimental Design: Patients were given erlotinib (150 mg/d). Tumor biopsies were done immediately before treatment and in a subgroup of patients after 6 weeks' treatment.
Results: Of 73 evaluable patients, 7 (10%) had partial response and 28 (38%) had stable disease. In 53 patients with baseline tumor samples, no relationship was observed between pretreatment levels of EGFR, phosphorylated (p)-EGFR, p-AKT, p-mitogen-activated protein kinase (MAPK), or p27 and clinical benefit (i.e., response, or stable disease ≥12 weeks). Tumors from 15 of 57 patients had high EGFR gene copy number, assessed using fluorescence in situ hybridization (FISH positive), 10 of whom had clinical benefit, compared with 5 of 42 FISH-negative patients. FISH-positive patients had longer median progression-free [137 versus 43 days, P = 0.002; hazard ratio (HR), 0.37] and overall (226 versus 106 days, P = 0.267; HR, 0.70) survival than FISH-negative patients. In paired biopsy samples from 14 patients, p-EGFR (P = 0.002), p-MAPK (P = 0.001), and Ki-67 (P = 0.025) levels were significantly reduced after 6 weeks' treatment. Apoptosis was significantly increased in patients with clinical benefit (P = 0.029), and may be a marker of clinical benefit.
Conclusion: In this study, EGFR FISH-positive status was associated with improved outcome after erlotinib therapy. Erlotinib led to reduced levels of p-EGFR, p-MAPK, and Ki-67, and stimulated apoptosis in tumor samples from patients with clinical benefit.
Local Recurrence in Mismatch Repair–Proficient Colon Cancer Predicted by an Infiltrative Tumor Border and Lack of CD8+ Tumor-Infiltrating Lymphocytes
Authors: Zlobec Inti , Terracciano Luigi M. , Lugli Alessandro 
Published: June 2008

Abstract
Purpose: The identification of colon cancer patients at high risk of local recurrence is necessary to improve the selection of patients for more tailored treatment protocols. The aim of this study was to develop a predictive model of local recurrence by assessing the independent predictive effect of 7 clinicopathologic features, 24 protein markers of tumor progression, and their multifeature combinations in mismatch repair–proficient colon cancers.
Experimental Design: Immunohistochemistry for 24 protein markers was done on 269 patients with complete clinicopathologic data. After univariate and multivariable analyses, independent predictors of local recurrence were identified and their multifeature combinations were analyzed. Kaplan-Meier and Cox proportional hazards regression were done for survival analysis.
Results: Local recurrence was observed in 119 patients (55.8%). Independent predictors of tumor recurrence were lymph node involvement (P = 0.006), absence of CD8+ tumor-infiltrating lymphocytes (TIL; P &lt; 0.001), and infiltrative tumor margin (P &lt; 0.001). This independent effect persisted after adjusting for adjuvant therapy. Risk of recurrence was 0.75 and the 5-year survival rate was 8.8% in patients with these three adverse features. Node-negative patients with an infiltrative tumor margin and absence of CD8+ TILs were identified as high risk with a probability of 0.55 for recurrence and a 60% 5-year survival rate. The remaining node-negative cases fared significantly better with risks ranging from 8% to 26% and 5-year survival rates reaching 97.6%.
Conclusions: An infiltrative tumor margin and absence of CD8+ TILs are highly predictive of local recurrence in node-negative mismatch repair–proficient colon cancer and may help to identify high-risk patients who may benefit from adjuvant chemotherapy.
Phosphodiesterase 11A (PDE11A) and Genetic Predisposition to Adrenocortical Tumors
Authors: Libé Rossella , Fratticci Amato , Coste Joel , Tissier Frédérique , Horvath Anelia , Ragazzon Bruno , Rene-Corail Fernande , Groussin Lionel , Bertagna Xavier , Raffin-Sanson Marie Laure , Stratakis Constantine A. , Bertherat Jérome 
Published: June 2008

Abstract
Purpose: We have reported previously nonsense inactivating mutations of the phosphodiesterase 11A (PDE11A) gene in patients with micronodular adrenocortical hyperplasia and Cushing syndrome. The aim of this study is to investigate the presence of somatic or germ-line PDE11A mutations in various types of adrenocortical tumors: ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), adrenocortical adenoma (ACA), and adrenocortical cancer (ACC).
Experimental Design: PDE11A was sequenced in 117 adrenocortical tumors and 192 controls subjects; immunohistochemistry for PDE11A and tumor cyclic AMP levels were studied in a subgroup of adrenocortical tumors.
Results: One PDE11A inactivating mutation (R307X) was found in one ACA, 22 germ-line missense variants (18.8%) were found in adrenocortical tumors, and only 11 missense variants (5.7%) were found in controls. By comparing the common mutations, a higher frequency of mutations in adrenocortical tumors than in age/sex-matched controls were observed [16% versus 10% in ACC, 19% versus 10% in ACA, and 24% versus 9% in AIMAH; odds ratio (OR), 3.53; P = 0.05]. Somatic DNA from adrenocortical tumors with missense variants showed a wild-type allelic loss. A significant difference between ACC and controls was observed for a polymorphism in exon 6 (E421E; OR, 2.1; P = 0.03) and three associated polymorphisms located in intron 10-exon 11-intron 11 (OR, 0.5; P = 0.01). In AIMAH/ACA, cyclic AMP levels were higher than in normal adrenals and decreased PDE11A immunostaining was present in adrenocortical tumors with PDE11A variants.
Conclusions: The present investigation of a large cohort of adrenocortical tumors suggests that PDE11A sequence defects predispose to a variety of lesions (beyond micronodular adrenocortical hyperplasia) and may contribute to the development of these tumors in the general population.
Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase, in Combination with High-Dose Cytarabine in Patients with Acute Myeloid Leukemia
Authors: Klisovic Rebecca B. , Blum William , Wei Xiaohui , Liu Shujun , Liu Zhongfa , Xie Zhiliang , Vukosavljevic Tamara , Kefauver Cheryl , Huynh LeNguyen , Pang Jiuxia , Zwiebel James A. , Devine Steven , Byrd John C. , Grever Michael R. , Chan Kenneth , Marcucci Guido 
Published: June 2008

Abstract
Purpose: Inhibition of ribonucleotide reductase reduces the availability of the endogenous pool of deoxycytidine and may increase cytarabine (AraC) cytotoxicity. We performed a phase I dose escalation trial of AraC combined with GTI-2040, a 20-mer antisense oligonucleotide shown in preclinical studies to decrease levels of the R2 subunit of ribonucleotide reductase, to determine the maximum tolerated dose in adults with relapsed/refractory acute myeloid leukemia.
Experimental Design: Twenty-three adults (ages 18-59 years) were enrolled in this dose escalation phase I trial, receiving high-dose AraC twice daily combined with infusional GTI-2040. An ELISA-based assay measured plasma and intracellular concentrations of GTI-2040. R2 protein changes were evaluated by immunoblotting in pretreatment and post-treatment bone marrow samples.
Results: The maximum tolerated dose was 5 mg/kg/d GTI-2040 (days 1-6) and 3 g/m2/dose AraC every 12 hours for 8 doses. Neurotoxicity was dose limiting. Eight patients (35%) achieved complete remission. Mean bone marrow intracellular concentration of GTI-2040 were higher at 120 hours than at 24 hours from the start of GTI-2040 (P = 0.002), suggesting intracellular drug accumulation over time. Reductions in bone marrow levels of R2 protein (&gt;50%) were observed at 24 and 120 hours. Higher baseline R2 protein expression (P = 0.03) and reductions after 24 hours of GTI-2040 (P = 0.04) were associated with complete remission.
Conclusions: GTI-2040 and high-dose AraC were coadministered safely with successful reduction of the intended R2 target and encouraging clinical results. The clinical efficacy of this combination will be tested in an upcoming phase II study.
The Relative Distribution of Membranous and Cytoplasmic Met Is a Prognostic Indicator in Stage I and II Colon Cancer
Authors: Ginty Fiona , Adak Sudeshna , Can Ali , Gerdes Michael , Larsen Melinda , Cline Harvey , Filkins Robert , Pang Zhengyu , Li Qing , Montalto Michael C. 
Published: June 2008

Abstract
Purpose: The association hepatocyte growth factor receptor (Met) tyrosine kinase with prognosis and survival in colon cancer is unclear, due in part to the limitation of detection methods used. In particular, conventional chromagenic immunohistochemistry (IHC) has several limitations including the inability to separate compartmental measurements. Measurement of membrane, cytoplasm, and nuclear levels of Met could offer a superior approach to traditional IHC.
Experimental Design: Fluorescent-based IHC for Met was done in 583 colon cancer patients in a tissue microarray format. Using curvature and intensity-based image analysis, the membrane, nuclear, and cytoplasm were segmented. Probability distributions of Met within each compartment were determined, and an automated scoring algorithm was generated. An optimal score cutpoint was calculated using 500-fold crossvalidation of a training and test data set. For comparison with conventional IHC, a second array from the same tissue microarray block was 3,3′-diaminobenzidine immunostained for Met.
Results: In crossvalidated and univariate Cox analysis, the membrane relative to cytoplasm Met score was a significant predictor of survival in stage I (hazard ratio, 0.16; P = 0.006) and in stage II patients (hazard ratio, 0.34; P ≤ 0.0005). Similar results were found with multivariate analysis. Met in the membrane alone was not a significant predictor of outcome in all patients or within stage. In the 3,3′-diaminobenzidine–stained array, no associations were found with Met expression and survival.
Conclusions: These data indicate that the relative subcellular distribution of Met, as measured by novel automated image analysis, may be a valuable biomarker for estimating colon cancer prognosis.