bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma and Cerebrospinal Fluid Pharmacokinetics of Imatinib after Administration to Nonhuman Primates
Authors: Neville Kathleen , Parise Robert A. , Thompson Patrick , Aleksic Alexander , Egorin Merrill J. , Balis Frank M. , McGuffey Leticia , McCully Cynthia , Berg Stacey L. , Blaney Susan M. 
Published: September 2005

AbstractPurpose: Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration.Experimental Design: Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liquid chromatography with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estimated using model-independent methods.Results: Peak plasma imatinib concentrations ranged from 6.4 to 9.5 μm after i.v. dosing and 0.8 to 2.8 μm after p.o. dosing. The mean ±SD area under the plasma concentration versus time curve was 2480 ±1340 μm·min and 1191 ±146 μm·min after i.v. and p.o. dosing, respectively. The terminal half-life was 529 ±167 min after i.v. dosing and 266 ±88 min after p.o. dosing. After i.v. dosing the steady state volume of distribution was 5.9 ±2.8 liter/kg, and the total body clearance was 12 ±5 ml/min/kg. The mean peak CSF concentration was 0.25 ±0.07 μm after i.v. dosing and 0.07 ±0.04 μm after p.o. dosing. The mean CSF:plasma area under the plasma concentration versus time curve ratio for all of the animals was 5% ±2%.Conclusions: There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration.
MUC1 and Nuclear β-Catenin Are Coexpressed at the Invasion Front of Colorectal Carcinomas and Are Both Correlated with Tumor Prognosis
Authors: Baldus Stephan E. , Mönig Stefan P. , Huxel Sandra , Landsberg Stephanie , Hanisch Franz-Georg , Engelmann Katja , Schneider Paul M. , Thiele Jürgen , Hölscher Arnulf H. , Dienes Hans P. 
Published: September 2005

Abstract
Purpose: Overexpression of MUC1 and cytosolic interaction of the mucin with β-catenin are claimed to be involved in colorectal carcinogenesis. In vitro data published recently suggest that MUC1 overexpression results in an increase of steady state levels of nuclear β-catenin. We tried to elucidate the coexpression of both molecules in colorectal cancer to demonstrate possible correlations with clinical, pathological, and prognostic data.
Experimental Design: An immunohistochemical double staining study was performed to characterize the expression and subcellular distribution of MUC1 and β-catenin in a series of 205 patients with colorectal carcinoma. The results were correlated with clinicopathological variables as well as overall survival.
Results: MUC1 was strongly expressed in the tumor center and at the invasion front in ∼50% of the cases. Similar results were obtained with regard to nuclear accumulation of β-catenin at the invasive tumor parts. MUC1 protein expression in the tumor center correlated significantly with a low grade of differentiation, and nuclear β-catenin in the tumor periphery was more frequent in carcinomas of the left colon and rectum. Overexpression of MUC1 and β-catenin, as well as their nuclear coexpression at the invasion front correlated with a worse overall survival in an univariate analysis. However, only pathological tumor-node-metastasis staging and MUC1 at the invasion front revealed as independent prognostic factors.
Conclusions: These results suggest that MUC1 and β-catenin are coexpressed at the invasion front of colorectal carcinomas and that this feature is associated with an accelerated course of disease and worse prognosis.
Evidence for Prostate Cancer-Associated Diagnostic Marker-1
Authors: Ohkia Akira , Hu Youji , Wang Min , Garcia Fernando U. , Stearns Mark E. 
Published: September 2005

Abstract
Purpose: The purpose of this study was to characterize a novel gene/protein associated with prostate cancer, termed prostate cancer-associated diagnostic marker-1 [PCADM-1 (Hu Y, Wang M, Garcia FU, Aoyaki K, Stearns ME. Identification of PCADM-1 as a novel diagnostic marker for prostate cancer, submitted for publication)].
Experimental Design and Results: Immunological studies revealed that rabbit polyclonal antibodies generated against recombinant PCADM-1 specifically recognize the protein in crude protein extracts from a variety of prostate cancer cell lines (i.e., PC-3 ML, LNCaP, DU145, and CPTX-1532) and prostate cancer tissue. Combined immunolabeling and in situ hybridization studies demonstrated that PCADM-1 mRNA was expressed by the luminal epithelial cells of prostate cancer glands and was not expressed by high-grade prostatic intraepithelial neoplasia or HPV-MLC7 cells. Immunolabeling studies of tissue arrays from biopsies of archival material (n = 200 samples) confirmed that PCADM-1 was expressed by the luminal epithelial cells of prostate cancer.
Conclusions: Taken together, the data suggest that PCADM-1 is a specific marker for human prostate cancer.
A Randomized Phase I and Pharmacological Trial of Sequences of 1,3-bis(2-Chloroethyl)-1-Nitrosourea and Temozolomide in Patients with Advanced Solid Neoplasms
Authors: Hammond Lisa A. , Eckardt John R. , Kuhn John G. , Gerson Stanton L. , Johnson Tom , Smith Lon , Drengler Ronald L. , Campbell Elizabeth , Weiss Geoffrey R. , Von Hoff Daniel D. , Rowinsky Eric K. 
Published: September 2005

Abstract
Purpose: O 6-alkylguanine-DNA alkyltransferase (AGAT) is modulated by methylating agents, which, in turn, abrogates nitrosourea resistance in preclinical studies. The feasibility of administering various sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TEM) in patients with advanced solid neoplasms was evaluated in this Phase I and pharmacological study to assess this premise in the clinical setting. The study also sought to determine the maximum tolerated dose (MTD) levels of BCNU and TEM as a function of Seq, to characterize the pharmacokinetic (PK) behavior of TEM administered both before and after BCNU, assess AGAT fluctuations in peripheral blood mononuclear cells (PBMCs), and seek preliminary evidence of anticancer activity.
Experimental Design: Sixty-three patients were randomized to receive treatment with oral TEM daily on days 1–5 and BCNU administered i.v., either on day 1 before TEM [Sequence (Seq) B→T] or day 5 after TEM (Seq T→B). Treatment was repeated every 6 weeks. Blood sampling for PK studies was performed on both days 1 and 5 of course one. PBMCs were sampled to evaluate major sequence-dependent effects on AGAT levels.
Results: Neutropenia and thrombocytopenia were the principal dose-limiting toxicities of the BCNU/TEM regimen. These effects were more prominent in patients receiving Seq T→B, resulting in a much lower MTD of 80/100 mg/m2/day compared with 150/110 mg/m2/day for Seq B→T. Notable antitumor activity was observed in patients with glioblastoma multiforme, sarcoma, and ovarian carcinoma. No sequence-dependent PK effects were noted to account for sequence-dependent toxicological effects. At the MTD level, AGAT activity in PBMCs decreased 3-fold, on average, and AGAT fluctuations did not appear to be sequence-dependent.
Conclusions: The principal toxicities of the BCNU/TEM regimen were neutropenia and thrombocytopenia, which were consistent and predictable, albeit sequence-dependent. Seq T→B was substantially more myelosuppressive, resulting in disparate MTDs and dose levels recommended for subsequent disease-directed evaluations (150/110 and 80/100 mg/m2/day for Seq B→T and T→B, respectively). Sequence-dependent differences in TEM PK do not account for this clinically relevant magnitude of sequence-dependent toxicity. The characteristics of the myelosuppressive effects of BCNU/TEM, the paucity of severe nonhematological toxicities, and antitumor activity at tolerable doses warrant disease-directed evaluations on this schedule.
Plasminogen Activator Inhibitor-1 as a Potential Marker for the Malignancy of Esophageal Squamous Cell Carcinoma
Authors: Sakakibara Takumi , Hibi Kenji , Kodera Yasuhiro , Ito Katsuki , Akiyama Seiji , Nakao Akimasa 
Published: September 2005

Abstract
Purpose and Experimental Design: To test whether plasminogen activator inhibitor-1 (PAI-1) can serve as a candidate marker for the malignancy of esophageal squamous cell carcinoma (SCC), we performed a quantitative reverse transcription-PCR for PAI-1 gene and evaluated the possible relationship between PAI-1 gene expression levels and clinicopathological findings in esophageal SCC.
Results: Significant increases in PAI-1 scores were observed in metastasis-positive esophageal SCCs (3.08 ± 0.80) compared with metastasis-negative ones (−0.31 ± 0.62; P = 0.0042). PAI-1 expression scores significantly increased with tumor stage (P = 0.05, ANOVA).
Conclusions: These results suggested that PAI-1 might serve as a new parameter for prediction of prognosis in esophageal SCC.
Detection of Prostate Cancer and Predicting Progression
Authors: Tricoli James V. , Schoenfeldt Mason , Conley Barbara A. 
Published: September 2005

Abstract
Carcinoma of the prostate is the second leading cause of male cancer-related death in the United States. Better indicators of prostate cancer presence and progression are needed to avoid unnecessary treatment, predict disease course, and develop more effective therapy. Numerous molecular markers have been described in human serum, urine, seminal fluid, and histological specimens that exhibit varying capacities to detect prostate cancer and predict disease course. However, to date, few of these markers have been adequately validated for clinical use. The purpose of this review is to examine the current status of these markers in prostate cancer and to assess the diagnostic potential for future markers from identified genes and molecules that display loss, mutation, or alteration in expression between tumor and normal prostate tissues. In this review we cite 91 molecular markers that display some level of correlation with prostate cancer presence, disease progression, cancer recurrence, prediction of response to therapy, and/or disease-free survival. We suggest criteria to consider when selecting a marker for further development as a clinical tool and discuss five examples of markers (chromogranin A, glutathione S-transferase π 1, prostate stem cell antigen, prostate-specific membrane antigen, and telomerase reverse transcriptase) that fulfill some of these criteria. Finally, we discuss how to conduct evaluations of candidate prostate cancer markers and some of the issues involved in the validation process.
Pak-1 Expression Increases with Progression of Colorectal Carcinomas to Metastasis
Authors: Carter Julia H. , Douglass Larry E. , Deddens James A. , Colligan Bruce M. , Bhatt Tejal R. , Pemberton Jackson O. , Konicek Susan , Hom Joanne , Marshall Mark , Graff Jeremy R. 
Published: September 2005

Abstract
Purpose: The p21-activated kinase-1 (Pak-1) promotes cell motility and invasiveness. Pak-1 is activated by the Rac, Rho, and Cdc42 small GTPases in response to a variety of stimuli including ras and phosphatidylinositol 3′-kinase/AKT pathway activation. Because Pak-1 plays a central role in regulating cell motility and invasiveness, we sought to determine whether Pak-1 may be involved in the malignant progression of colorectal carcinoma.
Experimental Design: Pak-1 expression was examined by immunohistochemistry in archived tissues from normal human colons, tubular and tubulovillous adenomas, invasive adenocarcinomas (stages I-III/IV), and lymph node metastases (184 total specimens from 38 patients). Specific cytoplasmic immunostaining was evaluated for overall intensity and uniformity to derive a combined histoscore (stain intensity × percentage of epithelium stained).
Results: Pak-1 expression was increased significantly with colorectal cancer progression from normal tissue to lymph node metastases (P &lt; 0.0001). Furthermore, Pak-1 expression was increased significantly in adenomas, invasive carcinomas, and lymph node metastases compared with normal colon (P &lt; 0.0001). Strikingly, Pak-1 expression was significantly higher in lymph node metastases than in invasive cancers, adenomas, or normal colon (P &lt; 0.0001). Moreover, in patients with multiple lesions representing different stages of disease, Pak-1 expression was increased specifically in the most advanced lesions.
Conclusions: This study demonstrates that Pak-1 expression is increased significantly with malignant progression of human colorectal carcinoma. These data, along with numerous functional studies demonstrating a central role for Pak-1 activity in tumor invasiveness and motility, implicate Pak-1 as an exciting target for therapy of colorectal carcinoma.
Molecular Marker Profiles Predict Locoregional Control of Head and Neck Squamous Cell Carcinoma in a Randomized Trial of Continuous Hyperfractionated Accelerated Radiotherapy
Authors: Buffa Francesca M. , Bentzen Søren M. , Daley Frances M. , Dische Stanley , Saunders Michele I. , Richman Paul I. , Wilson George D. 
Published: September 2005

Abstract
Purpose: Identification of factors that assist prediction of tumor response to radiotherapy may aid in refining treatment strategies and improving outcome. Possible association of molecular marker expression profiles with locoregional control of head and neck squamous cell carcinoma was investigated in a randomized trial of conventional versus continuous hyperfractionated accelerated radiotherapy (CHART).
Experimental Design: Tumor material was obtained from 402 patients. Immunohistochemistry was used to assess Ki-67, CD31, p53, Bcl-2, and cyclin D1 expression. A hierarchical clustering algorithm with a Bayesian information criterion was used to group tumors with similar marker expression; resulting expression profiles were then compared in terms of their difference in outcome after CHART and conventionally fractionated radiotherapy.
Results: Molecular marker profile was an independent prognostic factor for locoregional control. This was confirmed in multivariate analysis, including clinical variables such as tumor and nodal status, primary site, histological grade, age, and gender (P &lt; 0.001 and P = 0.006 for local and nodal relapse, respectively). In particular, Bcl-2-positive tumors responded significantly better than average in both arms of the trial. Tumors negative for p53- and Bcl-2, with high and randomly patterned Ki-67 expression, responded worse than average with no benefit from CHART. Tumors with similarly negative p53 and Bcl-2, but low Ki-67 staining, with an organized pattern, benefit significantly from CHART schedule.
Conclusions: This study demonstrates the potential of molecular profiles to predict radiotherapy response of head and neck squamous cell carcinoma and for treatment stratification. Distinct expression profiles correlate with three distinct clinical phenotypes, including good locoregional control, poor locoregional control, and an outcome strongly dependent upon fractionation schedule.
Prognostic Impact of ANX7-GTPase in Metastatic and HER2-Negative Breast Cancer Patients
Authors: Srivastava Meera , Bubendorf Lukas , Raffeld Mark , Bucher Christoph , Torhorst Jochen , Sauter Guido , Olsen Cara , Kallioniemi Olli P. , Eidelman Ofer , Pollard Harvey B. 
Published: September 2005

Abstract
Purpose: ANX7-GTPase located on chromosome 10q21 is significantly altered and associated with hormone-refractory metastatic prostate cancers. Therefore, we investigated whether levels of ANX7 correlate with breast cancer progression and survival
Experimental Design: A diagnostic tumor tissue microarray containing 525 human breast tissue specimens at different stages of the disease was assayed for ANX7 using immunocytochemical methods with ANX7 monoclonal antibody. A separate prognostic tumor tissue microarray containing 553 human breast tissue specimens annotated with clinicopathological parameters was assayed for ANX7, HER2, estrogen receptor, progesterone receptor, and p53 protein.
Results: We report here for the first time that the expression of ANX7-GTPase is significantly enhanced and associated with the presence of metastatic disease (P &lt; 0.0001) in the 525 human breast tissue specimens analyzed. Furthermore, using a separate 553 case retrospective prognostic tumor tissue microarray, we found that increased ANX7 expression is also significantly associated with poor overall patient survival (P &lt; 0.014). This is particularly true when restricted to patients in whom the BRE clinical grade is 2 (P &lt; 0.001) or for whom there is a lack of HER2 expression (P &lt; 0.002). Finally, Cox regression analysis shows that as the expression of ANX7 rises, the probability of survival decreases by more than 10-fold for those patients with HER2-negative tumors. These latter patients represented 66% of the population affected with breast cancer in this study.
Conclusions: High levels of ANX7 in tumor correlate strongly with poor survival of HER2-negative patients and the most aggressive forms of breast cancer. This is the first study to demonstrate that ANX7 antibody has the potential for development into an in vivo diagnostic and therapeutic tool. This simple and reliable immunohistochemical assay may therefore become an important biomarker for metastatic breast cancer diagnosis and management of HER2-negative breast tumor patients.
Antisense RNA Down-Regulation of bcl-2 Expression in DU145 Prostate Cancer Cells Does Not Diminish the Cytostatic Effects of G3139 (Oblimersen)
Authors: Raffo Anthony , Lai Johnathan C. , Stein C. A. , Miller Paul , Scaringe Steven , Khvorova Anastasia , Benimetskaya Luba 
Published: September 2005

Abstract
Purpose: Inhibition of the function of the bcl-2 protein has been postulated to sensitize cells to cytotoxic chemotherapy, and thus provides an attractive target for investigative therapies. G3139, a phosphorothioate antisense oligonucleotide targeted to the initiation codon region of the bcl-2 mRNA, is currently being evaluated in several Phase II and Phase III clinical trials. However, the mechanism of action of this molecule appears to depend on a combination of antisense plus nonantisense events. Indeed, the very idea that bcl-2 is a critical target is, at least in part, an extrapolation from experiments in which intracellular bcl-2 protein concentrations have been dramatically increased, yielding chemoresistant cells.
Experimental Design: In this work, we down-regulated the expression of bcl-2 protein by 80–90% by two different antisense RNA strategies (antisense RNA and small interfering RNA) in DU145 prostate cancer cells.
Results: Even after down-regulation of bcl-2 protein expression by either one of these strategies, the cellular phenotype induced by subsequent G3139 treatment (inhibition of cellular growth and the generation of reactive oxygen species) was essentially identical to that induced in mock-infected or wild-type DU145 cells in which bcl-2 protein expression had not been down-regulated previously.
Conclusions: These results strongly suggest that bcl-2 expression in DU145 cells is not strongly associated with the prolife phenotype and that the mechanism by which G3139 produces its cytostatic effects in this cell line is bcl-2 independent.
Identification of Altered Protein Expression and Post-Translational Modifications in Primary Colorectal Cancer by Using Agarose Two-Dimensional Gel Electrophoresis
Authors: Tomonaga Takeshi , Matsushita Kazuyuki , Yamaguchi Seiko , Oh-Ishi Masamichi , Kodera Yoshio , Maeda Tadakazu , Shimada Hideaki , Ochiai Takenori , Nomura Fumio 
Published: September 2005

Abstract
Purpose: Although numerous proteome studies have been performed recently to identify cancer-related changes in protein expression, only a limited display of relatively abundant proteins has been identified. The aim of this study is to identify novel proteins as potential tumor markers in primary colorectal cancer tissues using a high-resolution two-dimensional gel electrophoresis (2-DE).
Experimental Design: 2-DE using an agarose gel for isoelectric focusing was used to compare protein profiling of 10 colorectal cancer tissues and adjacent normal mucosa. Altered expression and post-translational modification of several proteins were examined using Western blot analysis and immunohistochemistry.
Results: Ninety-seven proteins of 107 spots (90.7%) that were differentially expressed between matched normal and tumor tissues were identified by mass spectrometry. Among them, 42 unique proteins (49 spots) significantly increased or decreased in the tumors. They include eukaryotic translation initiation factor 4H, inorganic pyrophosphatase, anterior gradient 2 homologue, aldolase A, and chloride intracellular channel 1, whose elevated expression in tumor tissues was confirmed by Western blot analysis and immunohistochemistry. Interestingly, only isoform 1 of two transcript variants of eukaryotic translation initiation factor 4H was greatly up-regulated in most of the tumor tissues. Moreover, post-translational modifications of the prolyl-4-hydroxylase β subunit and annexin A2 also were identified.
Conclusions: We identified several novel proteins with altered expression in primary colorectal cancer using agarose 2-DE. This method is a powerful technique with which to search for not only quantitative but also qualitative changes in a biological process of interest and may contribute to the deeper understanding of underlying mechanisms of human cancer.
Second Round Results of the Finnish Population-Based Prostate Cancer Screening Trial
Authors: Mäkinen Tuukka , Tammela Teuvo L. J. , Stenman Ulf-Håkan , Määttänen Liisa , Aro Jussi , Juusela Harri , Martikainen Paula , Hakama Matti , Auvinen Anssi 
Published: September 2005

AbstractPurpose: Large randomized trials provide the only valid means of quantifying the benefits and drawbacks of prostate-specific antigen (PSA) screening, but the follow-up of ongoing studies is still too short to allow evaluation of mortality. We report here the intermediate indicators of screening efficacy from the second round of the Finnish trial.Experimental Design: The Finnish trial, with ∼80,000 men in the target population, is the largest component in the European Randomized Study of Screening for Prostate Cancer. The first round was completed in 1996–1999. Each year 8,000 men 55–67 years of age were randomly assigned to the screening arm, and the rest formed the control arm. Men randomized to the screening arm in 1996 were reinvited 4 years later, in 2000, and PSA was determined.Results: Of the eligible 6415 men, 4407 (69%) eventually participated in the second round of screening. Of the first-round participants, up to 84% (3833 of 4556) attended rescreening. A total of 461 screenees (10.5%) had PSA levels of ≥4 μg/liter. Altogether, 97 cancers were found, yielding an overall detection rate of 2.2% (97 of 4407). Seventy-nine cases were found among the 3833 second-time screenees (detection rate 2.1%) and 18 in those 574 men (3.1%) who had not participated previously. A PSA of ≥4 μg/liter, but negative biopsy in the first screening round was associated with an up to 9-fold risk of cancer in rescreening relative to those with lower PSA levels at baseline. Ninety-one (94%) of all of the detected cancers were clinically localized.Conclusions: As surrogate measures of an effective screening program, both compliance as well as the overall and advanced prostate cancer detection rates remained acceptable. Men defined as screen-positive but with a negative confirmation of cancer at prevalence screen formed a high-risk group at rescreening.