bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excision Repair Cross-Complementation Group 1 Polymorphism Predicts Overall Survival in Advanced Non-Small Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy
Authors: Zhou Wei , Gurubhagavatula Sarada , Liu Geoffrey , Park Sohee , Neuberg Donna S. , Wain John C. , Lynch Thomas J. , Su Li , Christiani David C. 
Published: September 2005

Abstract
DNA repair is a critical mechanism of resistance to platinum-based chemotherapy. Excision repair cross-complementation group 1 (ERCC1) is the lead enzyme in the nucleotide excision repair process. Increased ERCC1 mRNA levels are related directly to platinum resistance in various cancers. We examined the association between two polymorphisms of ERCC1, codon 118 C/T and C8092A, which are associated with altered ERCC1 mRNA levels and mRNA stability, and overall survival (OS) in 128 advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. The two polymorphisms were in linkage disequilibrium. There was a statistically significant association between the C8092A polymorphism and OS (P = 0.006, by log-rank test), with median survival times of 22.3 (C/C) and 13.4 (C/A or A/A) months, respectively, suggesting that any copies of the A allele were associated with poor outcome. No statistically significant association was found for the codon 118 polymorphism and OS (P = 0.41, by log-rank test), with median survival times of 19.9 (T/T), 16.1 (C/T), and 13.3 (C/C) months, respectively. In conclusion, the ERCC1 C8092A polymorphism may be a useful predictor of OS in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.
A Phase I Trial of the Dual Farnesyltransferase and Geranylgeranyltransferase Inhibitor L-778,123 and Radiotherapy for Locally Advanced Pancreatic Cancer
Authors: Martin Neil E. , Brunner Thomas B. , Kiel Krystina D. , DeLaney Thomas F. , Regine William F. , Mohiuddin Mohammed , Rosato Ernest F. , Haller Daniel G. , Stevenson James P. , Smith Debbie , Pramanik Barnali , Tepper Joel , Tanaka Wesley K. , Morrison Briggs , Deutsch Paul , Gupta Anjali K. , Muschel Ruth J. , McKenna W. Gillies , Bernhard Eric J. , Hahn Stephen M. 
Published: September 2005

Abstract
Purpose: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer.
Experimental Design: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2.
Results: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated.
Conclusions: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.
On the Role of Melanoma-Specific CD8+ T-Cell Immunity in Disease Progression of Advanced-Stage Melanoma Patients
Authors: van Oijen Monique , Bins Adriaan , Elias Sjoerd , Sein Johan , Weder Pauline , de Gast Gijsbert , Mallo Henk , Gallee Maarten , van Tinteren Harm , Schumacher Ton , Haanen John 
Published: September 2005

AbstractCytotoxic T-cell immunity directed against melanosomal differentiation antigens is arguably the best-studied and most prevalent form of tumor-specific T-cell immunity in humans. Despite this, the role of T-cell responses directed against melanosomal antigens in disease progression has not been elucidated. To address this issue, we have related the presence of circulating melanoma-specific T cells with disease progression and survival in a large cohort of patients with advanced-stage melanoma who had not received prior treatment. In 42 (68%) of 62 patients, melanoma-specific T cells were detected, sometimes in surprisingly large numbers. Disease progression during treatment was more frequent in patients with circulating melanoma-specific T cells, and mean survival of patients with circulating melanoma-specific T cells was equal to the survival of patients without melanoma-specific T cells. These data suggest that the induction of melanosomal differentiation antigen-specific T-cell reactivity in advanced stage melanoma is a late event most likely due to antigen load and spreading and is not accompanied by a clinically significant antitumor effect. These melanoma-specific T cells may be functionally distinct from T cells raised during spontaneous regression or up vaccination.
Met Proto-Oncogene and Insulin-Like Growth Factor Binding Protein 3 Overexpression Correlates with Metastatic Ability in Well-Differentiated Pancreatic Endocrine Neoplasms
Authors: Hansel Donna E. , Rahman Ayman , House Michael , Ashfaq Raheela , Berg Karin , Yeo Charles J. , Maitra Anirban 
Published: September 2005

Abstract
Pancreatic endocrine neoplasms are neoplastic proliferations of islet cells or islet cell precursors and are capable of secreting a variety of synthetic products, including insulin, glucagon, gastrin, and vasoactive intestinal peptide. The biological behavior of pancreatic endocrine neoplasms is often unpredictable, and there are few reliable histopathologic criteria reliably correlating with metastatic ability. We have used the Affymetrix U133 GeneChip set (HG_U133 A and B; Affymetrix; Santa Clara, CA) representing ∼33,000 characterized transcripts to examine global gene expression profiles from well-differentiated nonmetastatic (n = 5) and metastatic (n = 7) pancreatic endocrine neoplasms to determine molecular markers that predict disease progression. Microarray hybridization data were normalized using the GeneLogic GeneExpress Software System to identify differentially up- and down-regulated genes in metastatic versus nonmetastatic pancreatic endocrine neoplasms. Using a 3-fold change in gene expression as a threshold, we have identified 65 overexpressed and 57 underexpressed genes in metastatic pancreatic endocrine neoplasms as compared with nonmetastatic pancreatic endocrine neoplasms. Several classes of genes, including growth factors and growth factor-related molecules (IGFBP1, IGFBP3, and MET), developmental factors (TBX3 and MEIS2), cytoskeletal factors (β 1 tubulin and ACTN2), cholesterol homeostasis mediators (LRP5, SLC27A2, and RXRG), intracellular signaling pathway mediators (DYRK1A, PKIB, and AK2), methyltransferases (MGMT and GAMT), and DNA repair and regulatory molecules (CHEK1 and ZNF198), were identified as differentially over- or underexpressed via this method. Immunohistochemical validation of microarray data were performed for two overexpressed genes, namely, the met proto-oncogene (MET) and insulin-like growth factor binding protein 3 (IGFBP3) with tissue microarrays of nonmetastatic (n = 24) and metastatic (n = 15) pancreatic endocrine neoplasms. Increased expression of IGFBP3 was confirmed in metastatic versus nonmetastatic pancreatic endocrine neoplasms (12 of 15, 80% versus 10 of 24, 42%), as well as in lymph node (6 of 7, 86%) and liver (9 of 9, 100%) metastases. Similarly, overexpression of MET was confirmed in metastatic versus nonmetastatic pancreatic endocrine neoplasms (5 of 15, 33% versus 4 of 24, 17%), as well as in lymph node metastases (4 of 7, 57%) and liver metastases (5 of 9, 56%). The majority of genes that demonstrated altered expression has not been previously identified as differentially expressed in metastatic pancreatic endocrine neoplasm lesions and may therefore represent newly identified molecules in the progression of these lesions.
A Phase I Trial of TNFerade Biologic in Patients with Soft Tissue Sarcoma in the Extremities
Authors: Mundt Arno J. , Vijayakumar Srinivasan , Nemunaitis John , Sandler Alan , Schwartz Herbert , Hanna Nader , Peabody Terrence , Senzer Neil , Chu Karen , Rasmussen Camilla S. , Kessler Paul D. , Rasmussen Henrik S. , Warso Michael , Kufe Donald W. , Gupta Tapas Das , Weichselbaum Ralph R. 
Published: September 2005

Abstract
Purpose: TNFerade is a second-generation replication-deficient adenovector carrying a transgene encoding human tumor necrosis factor α under control of a radiation- induced promoter. The objective of this study was to assess the tolerance of combining TNFerade and radiation therapy in patients with soft tissue sarcomas of the extremity.
Experimental Design: TNFerade was administered in combination with single-daily fractionated radiation therapy in 14 patients with soft tissue sarcoma of the extremities. Three escalating dose levels of TNFerade (4 × 109 −4 × 1011 particle units) were planned, given in 1 log increments by intratumoral injections, twice weekly during week 1 and once weekly during weeks 2–5 of radiation therapy.
Results: TNFerade was well tolerated with no dose-limiting toxicities noted. Grade 1–2 chills (50.0%), fever (43.0%), fatigue (36.0%), and flu-like symptoms (21.0%) were the most common side effects. Serum-tumor necrosis factor α levels were low in all of the patients (&lt;15 pg/mL). No patients had virus-detected blood, sputum, or urine cultures. Of the 13 evaluable patients, 11 received TNFerade preoperatively, and 2 received the treatment for palliation. Eleven patients (85%) showed objective or pathological tumor responses (2 complete and 9 partial), and 1 had stable disease. Partial responses were achieved despite some of these tumors being very large (up to 675 cm2). Of the 11 patients who underwent surgery, 10 (91%) showed a pathological complete response/partial response.
Conclusion: TNFerade + radiation therapy was well tolerated in the treatment of patients with soft-tissue sarcoma of the extremity. The high number of objective responses observed warrants additional studies of this approach in a larger controlled prospective trial.
Molecular Profiling of Inflammatory Breast Cancer
Authors: Bièche Ivan , Lerebours Florence , Tozlu Sengül , Espie Marc , Marty Michel , Lidereau Rosette 
Published: September 2005

Abstract
Purpose: Inflammatory breast cancer (IBC) is a rare but particularly aggressive form of primary breast cancer. The molecular mechanisms responsible for IBC are largely unknown.
Experimental Design: To obtain further insight into the molecular pathogenesis of IBC, we used real-time quantitative reverse transcription (RT)-PCR to quantify the mRNA expression of 538 selected genes in IBC relative to non-IBC.
Results: Twenty-seven (5.0%) of the 538 genes were significantly up-regulated in IBC compared with non-IBC. None were down-regulated. The 27 up-regulated genes mainly encoded transcription factors (JUN, EGR1, JUNB, FOS, FOSB, MYCN, and SNAIL1), growth factors (VEGF, DTR/HB-EGF, IGFBP7, IL6, ANGPT2, EREG, CCL3/MIP1A, and CCL5/RANTES) and growth factor receptors (TBXA2R, TNFRSF10A/TRAILR1, and ROBO2). We also identified a gene expression profile, based on MYCN, EREG, and SHH, which discriminated subgroups of IBC patients with good, intermediate, and poor outcome.
Conclusion: Our study has identified a limited number of signaling pathways that require inappropriate activation for IBC development. Some of the up-regulated genes identified here could offer useful diagnostic or prognostic markers and could form the basis of novel therapeutic strategies.
DNA Array-Based Gene Profiling in Tumor Immunology
Authors: Mocellin Simone , Wang Ena , Panelli Monica , Pilati Pierluigi , Marincola Francesco M. 
Published: September 2005

AbstractRecent advances in tumor immunology have fostered the clinical implementation of different immunotherapy modalities. However, the alternate success of such regimens underscores the fact that the molecular mechanisms underlying tumor immune rejection are still poorly understood. Given the complexity of the immune system network and the multidimensionality of tumor–host interactions, the comprehension of tumor immunology might greatly benefit from high-throughput DNA array analysis, which can portray the molecular kinetics of immune response on a genome-wide scale, thus accelerating the accumulation of knowledge and ultimately catalyzing the development of new hypotheses in cell biology. Although in its infancy, the implementation of DNA array technology in tumor immunology studies has already provided investigators with novel data and intriguing hypotheses on the cascade of molecular events leading to an effective immune response against cancer. Although the principles of DNA array-based gene profiling techniques have become common knowledge, the need for mastering this technique to produce meaningful data and correctly interpret this enormous output of information is critical and represents a tremendous challenge for investigators. In the present work, we summarize the main technical features and critical issues characterizing this powerful laboratory tool and review its applications in the fascinating field of cancer immunogenomics.
Aberrant Methylation of
DPYD
Promoter,
DPYD
Expression, and Cellular Sensitivity to 5-Fluorouracil in Cancer Cells
Authors: Noguchi Takuya , Tanimoto Keiji , Shimokuni Tatsushi , Ukon Kei , Tsujimoto Hiroaki , Fukushima Masakazu , Noguchi Tsuyoshi , Kawahara Katsunobu , Hiyama Keiko , Nishiyama Masahiko 
Published: September 2005

Abstract
Purpose: Dihydropyrimidine dehydrogenase (DPD), the initial rate-limiting enzyme in the degradation of 5-fluorouracil (5-FU), is known to be a principal factor in clinical responses to the anticancer agent 5-FU, and various reports have clearly demonstrated that DPD activity is closely correlated to mRNA levels. However, the regulatory mechanisms of DPD gene (DPYD) expression remain unclear. In this study, the regulatory mechanisms have been intensively studied.
Experimental Design and Results: A subcloned 3.0-kb fragment of the 5′ region of DPYD contains a total of 60 CpG sites, suggesting that methylation status may affect the repression of DPYD. The clone showed various promoter activities that were largely correlated with mRNA levels in most cell lines, except HSC3 and HepG2. Bisulfite sequencing analysis revealed that various CpG sites around the transcription start site were abnormally methylated in cells with low DPYD expression: Reversal of hypermethylation by 5-azacytidine treatment significantly increased DPYD expression in HSC3 and HepG2 cells that showed strong promoter activity. In HepG2, in vitro methylation of the DPYD promoter directly decreased promoter activity, and 5-azacytidine treatment restored higher DPYD expression in a dose- and time-dependent manner, along with decreased sensitivity to 5-FU.
Conclusions: We found that DPD activity was controlled, at least in part, at the transcription level of DPYD and that aberrant methylation of the DPYD promoter region acted as one of the repressors of DPYD expression and affected sensitivity to 5-FU in cancer cells. Our new results could lead to a more precise understanding of the molecular basis of 5-FU response.
Fusion Cell Vaccination of Patients with Metastatic Breast and Renal Cancer Induces Immunological and Clinical Responses
Authors: Avigan David , Vasir Baldev , Gong Jianlin , Borges Virginia , Wu Zekui , Uhl Lynne , Atkins Michael , Mier James , McDermott David , Smith Therese , Giallambardo Nancy , Stone Carolyn , Schadt Kim , Dolgoff Jennifer , Tetreault Jean-Claude , Villarroel Marisa , Kufe Donald 
Published: September 2005

AbstractPurpose: Dendritic cells (DCs) are potent antigen-presenting cells that are uniquely capable of inducing tumor-specific immune responses. We have conducted a Phase I trial in which patients with metastatic breast and renal cancer were treated with a vaccine prepared by fusing autologous tumor and DCs.Experimental Design: Accessible tumor tissue was disrupted into single cell suspensions. Autologous DCs were prepared from adherent peripheral blood mononuclear cells that were obtained by leukapheresis and cultured in granulocyte macrophage colony-stimulating factor, interleukin 4, and autologous plasma. Tumor cells and DCs were cocultured in the presence of polyethylene glycol to generate the fusions. Fusion cells were quantified by determining the percentage of cells that coexpress tumor and DC markers. Patients were vaccinated with fusion cells at 3-week intervals and assessed weekly for toxicity, and tumor response was assessed at 1, 3, and 6 months after completion of vaccination.Results: The vaccine was generated for 32 patients. Twenty-three patients were vaccinated with 1 × 105 to 4 × 106 fusion cells. Fusion cells coexpressed tumor and DC antigens and stimulated allogeneic T-cell proliferation. There was no significant treatment-related toxicity and no clinical evidence of autoimmunity. In a subset of patients, vaccination resulted in an increased percentage of CD4 and CD8+ T cells expressing intracellular IFN-γ in response to in vitro exposure to tumor lysate. Two patients with breast cancer exhibited disease regressions, including a near complete response of a large chest wall mass. Five patients with renal carcinoma and one patient with breast cancer had disease stabilization.Conclusions: Our findings demonstrate that fusion cell vaccination of patients with metastatic breast and renal cancer is a feasible, nontoxic approach associated with the induction of immunological and clinical antitumor responses.
Inhibition of Hepatocellular Carcinomas
in vitro
and Hepatic Metastases
in vivo
in Mice by the Histone Deacetylase Inhibitor HA-But
Authors: Coradini Danila , Zorzet Sonia , Rossin Raffaella , Scarlata Ignazio , Pellizzaro Cinzia , Turrin Claudia , Bello Michele , Cantoni Silvia , Speranza Annalisa , Sava Gianni , Mazzi Ulderico , Perbellini Alberto 
Published: September 2005

Abstract
Purpose: The purpose is to evaluate the CD44-mediated cellular targeting of HA-But, a hyaluronic acid esterified with butyric acid (But) residues, to hepatocellular carcinoma cell lines in vitro and to hepatic tumor metastases in vivo.
Experimental Design: In vitro, the CD44-dependent cytotoxicity in two human hepatocellular carcinoma cell lines (HepB3 and HepG2) with high and low CD44 expression was investigated; in vivo, the effect on liver metastases originating from intrasplenic implants of Lewis lung carcinoma (LL3) or B16-F10 melanoma in mice was compared with the pharmacokinetics of organ and tissue distribution using different routes of administration.
Results: HepB3 and HepG2 cell lines showed different expression of CD44 (78 and 18%, respectively), which resulted in a CD44-dependent HA-But inhibitory effect as demonstrated also by the uptake analysis performed using radiolabeled HA-But (99mTc-HA-But). Pharmacokinetic studies showed different rates of 99mTc-HA-But distribution according to the route of administration (i.v., i.p., or s.c.): very fast (a few minutes) after i.v. treatment, with substantial accumulation in the liver and spleen; relatively slow after i.p. or s.c. treatment, with marked persistence of the drug at the site of injection. The effect of s.c. and i.p. treatment with HA-But on liver metastases originating from intrasplenic implants of LL3 carcinoma or B16-F10 melanoma (both CD44-positive: 68 and 87%, respectively), resulted in 87 and 100% metastases-free animals, respectively (regardless of the route of administration), and a significant prolongation of the life expectancy compared with control groups.
Conclusions: HA-But tends to concentrate in the liver and spleen and appears to be a promising new drug for the treatment of intrahepatic tumor lesions.
Reg IV: A Promising Marker of Hormone Refractory Metastatic Prostate Cancer
Authors: Gu Zhennan , Rubin Mark A. , Yang Yu , Deprimo Samuel E. , Zhao Hongjuan , Horvath Steven , Brooks James D. , Loda Massimo , Reiter Robert E. 
Published: September 2005

Abstract
The diagnosis and management of prostate cancer is hampered by the absence of markers capable of identifying patients with metastatic disease. In order to identify potential new markers for prostate cancer, we compared gene expression signatures of matched androgen-dependent and hormone refractory prostate cancer xenografts. One candidate gene overexpressed in a hormone refractory xenograft was homologous to the regenerating protein gene family, a group of secreted proteins expressed in the gastrointestinal tract and overexpressed in inflammatory bowel disease and cancer. This gene, Reg IV, was confirmed to be differentially expressed in the LAPC-9 hormone refractory xenograft. Consistent with its up-regulation in a hormone refractory xenograft, it is expressed in several prostate tumors after neoadjuvant hormone ablation therapy. As predicted by its sequence homology, it is secreted from transiently transfected cells. It is also expressed strongly in a majority of hormone refractory metastases represented on two high-density tissue microarrays. In comparison, it is not expressed by any normal prostate specimens and only at low levels in ∼40% of primary tumors. These data support Reg IV as a candidate marker for hormone refractory metastatic prostate cancer.
Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells
Authors: Mondesire Wallace H. , Jian Weiguo , Zhang Haixia , Ensor Joe , Hung Mien-Chie , Mills Gordon B. , Meric-Bernstam Funda 
Published: September 2005

Abstract
Purpose: The serine-threonine kinase mammalian target of rapamycin has emerged as a potential target for cancer therapy. Rapamycin and rapamycin analogs are undergoing clinical trials and have induced clinical responses in a subgroup of patients. Rapamycin has also been reported to enhance the efficacy of several cytotoxic agents. The aim of this study was to determine the nature of the interactions between rapamycin and chemotherapeutic agents used as first- and second-line agents against breast cancer.
Experimental Design: We performed a multiple drug effect/combination index isobologram analysis in cells sensitive and resistant to rapamycin alone in vitro, and we evaluated the in vivo efficacy of combination therapy in a rapamycin-sensitive model.
Results: In vitro, synergistic interactions were observed in combinations with paclitaxel, carboplatin, and vinorelbine. Additive effects were observed in combinations with doxorubicin and gemcitabine. Rapamycin dramatically enhanced paclitaxel- and carboplatin-induced apoptosis. This effect was sequence dependent and mediated at least partly through caspase activation. Furthermore, rapamycin enhanced chemosensitivity to paclitaxel and carboplatin in HER2/neu-overexpressing cells, suggesting a potential approach to these poorly behaving tumors. Cell lines that are resistant to the growth-inhibitory effect of rapamycin were also resistant to rapamycin-mediated chemosensitization. In vivo, rapamycin combined with paclitaxel resulted in a significant reduction in tumor volume compared with either agent alone in rapamycin-sensitive tumors.
Conclusions: Rapamycin potentiates the cytotoxicity of selected chemotherapeutic agents in cell lines sensitive to the effects of rapamycin due to aberrations in the phosphatidylinositol 3′-kinase/Akt pathway, suggesting that combination therapy may be effective in patients selected for aberrations in this pathway.