bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of Genomics-Based Prognostic Tests in Malignant Pleural Mesothelioma
Authors: Gordon Gavin J. , Rockwell Graham N. , Godfrey Paul A. , Jensen Roderick V. , Glickman Jonathan N. , Yeap Beow Y. , Richards William G. , Sugarbaker David J. , Bueno Raphael 
Published: September 2005

Abstract
Purpose: Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm with limited pretreatment prognostication strategies. In this report, we examine the accuracy of a previously proposed prognostic test in an independent cohort of MPM patients. This test uses simple ratios of gene expression levels to provide a novel prognostication scheme.
Experimental Design: Gene expression data using high-density oligonucleotide microarrays (∼22,000 genes) were obtained for a new cohort of human MPM tumors from patients undergoing similar treatments (n = 39). The relative expression levels for specific genes were also determined using real-time quantitative reverse transcription-PCR. We also used a subset of these tumors associated with widely divergent patient survival (n = 23) as a training set to identify new treatment-specific candidate prognostic molecular markers and gene ratio–based prognostic tests. The predictive nature of these newly discovered markers and gene ratio–based prognostic tests were then examined in an independent group of tumors (n = 52) using microarray data and quantitative reverse transcription-PCR.
Results: Previously described MPM prognostic genes and gene ratio–based prognostic tests predicted clinical outcome in 39 independent MPM tumor specimens in a statistically significant manner. Newly discovered treatment-specific prognostic genes and gene ratio–based prognostic tests were highly accurate and statistically significant when examined in an independent group of 52 tumors from patients undergoing similar treatment.
Conclusions: The data support the use of gene ratios in translating gene expression data into easily reproducible, statistically validated clinical tests for the prediction of outcome in MPM.
Aromatase Inhibition: Translation into a Successful Therapeutic Approach
Authors: Geisler Jürgen , Lønning Per Eystein 
Published: September 2005

Abstract
The development of the novel third-generation aromatase inhibitors and inactivators for breast cancer treatment is one of the most successful contemporary achievements in cancer therapy. Parallel to studies evaluating toxicity and clinical efficacy in metastatic disease, the endocrine effects of multiple compounds were evaluated, leading to the identification of the highly potent third-generation aromatase inhibitors based on estrogen deprivation and aromatase inhibition in vivo. Thus, translational studies have been of vital importance identifying the unique characteristics of these compounds. Whereas first- and second-generation aromatase inhibitors inhibit estrogen synthesis in vivo by up to 90%, the third-generation compounds anastrozole, exemestane, and letrozole were found to cause ≥98% aromatase inhibition. This article summarizes and discusses the “translational research” that provided the background for the implementation of the third-generation aromatase inhibitors and inactivators into large clinical trials. The need for future translational research exploiting the mechanisms of resistance to these compounds for future improvement of endocrine therapy is emphasized.
The Transforming Growth Factor-β Family Members Bone Morphogenetic Protein-2 and Macrophage Inhibitory Cytokine-1 as Mediators of the Antiangiogenic Activity of N-(4-Hydroxyphenyl)Retinamide
Authors: Ferrari Nicoletta , Pfeffer Ulrich , Dell'Eva Raffaella , Ambrosini Claudia , Noonan Douglas M. , Albini Adriana 
Published: September 2005

Abstract
Purpose: Tumor growth appears to be an angiogenesis-dependent process. N-(4-hydroxyphenyl)retinamide (fenretinide; 4HPR) has been found to inhibit and/or prevent tumor growth under diverse conditions. Although 4HPR is antiangiogenic, the molecular mechanisms of this effect remain largely unknown.
Experimental Design: Endothelial cells were treated with 4HPR in vitro to study the effects on migration, invasion, and organization, as well as gene expression by microarray and quantitative PCR studies. In vivo angiogenesis was evaluated in the Matrigel model.
Results: 4HPR treatment substantially modified the biological activities of endothelial cells, repressing their capacity to migrate, invade, and organize into capillary-like structures. The inhibition of invasion induced by 4HPR was also associated with decreased activities of the metalloproteases matrix metalloproteinase-2 and CD13/APN. Using oligonucleotide microarrays, we observed that bone morphogenetic protein-2 and macrophage inhibitory cytokine-1, two multifunctional cytokines of the transforming growth factor-β family that regulate the growth, differentiation, apoptosis, and matrix accumulation of a variety of cells, are up-regulated in vitro by 4HPR. Both these molecules specifically inhibited endothelial cell growth, migration, and invasion in vitro and suppressed angiogenesis in the Matrigel plug assay in vivo. Blocking antibodies to bone morphogenetic protein-2 were able to reverse the suppressive effects of 4HPR in vitro and in vivo.
Conclusions: These data support the conclusion that 4HPR inhibits tumor growth by repression of new vessel growth and identify novel points of regulation of angiogenesis in transforming growth factor-β family proteins.
ERCC1 Codon 118 Polymorphism Is a Predictive Factor for the Tumor Response to Oxaliplatin/5-Fluorouracil Combination Chemotherapy in Patients with Advanced Colorectal Cancer
Authors: Viguier Jérôme , Boige Valérie , Miquel Catherine , Pocard Marc , Giraudeau Bruno , Sabourin Jean-Christophe , Ducreux Michel , Sarasin Alain , Praz Françoise 
Published: September 2005

Abstract
Purpose: The aim of our study was to assess whether the polymorphism of the nucleotide excision repair enzyme, excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), had an effect on the tumor response in patients treated with standard chemotherapy regimens for a metastatic colorectal cancer. We have studied the synonymous polymorphism that causes a single nucleotide change C to T at codon 118 converting a codon of common usage (AAC) to a less used codon (AAT), both coding asparagine. This change results in a decreased ERCC1 gene expression, which impairs repair activity.
Experimental Design: Ninety-one patients with a median age of 55.1 years treated for a metastatic colorectal cancer were included in our retrospective study. The ERCC1 polymorphism was analyzed in the normal tissue of all patients.
Results: Twenty (22%) were homozygous for AAC codon (C/C genotype), 30 were (33%) homozygous for AAT codon (T/T genotype), and 41 (45%) were heterozygous (C/T genotype). The objective response rate to oxaliplatin in combination with 5-fluorouracil (5-FU) was significantly higher in the T/T genotype group compared with the C/T and the C/C genotype groups (61.9%, 42.3%, and 21.4%, respectively; P = 0.018). By contrast, no significant difference was observed when patients were treated with either 5-FU alone (45%, 29.2%, and 33.3%, respectively; P = 0.407) or in combination with irinotecan (46.1%, 25.0%, and 27.3%, respectively; P = 0.305).
Conclusions: Our observations allowed us to define the first useful predictive criterion for oxaliplatin/5-FU response in patients with metastatic colorectal cancer.
First Clinical Experience with α-Emitting Radium-223 in the Treatment of Skeletal Metastases
Authors: Nilsson Sten , Larsen Roy H. , Fosså Sophie D. , Balteskard Lise , Borch Kari W. , Westlin Jan-Erik , Salberg Gro , Bruland Øyvind S. 
Published: September 2005

Abstract
Purpose: The main goals were to study the safety and tolerability of the α-emitter radium-223 (223Ra) in breast and prostate cancer patients with skeletal metastases. In addition, pain palliation was evaluated.
Experimental Design: Fifteen prostate and 10 breast cancer patients enrolled in a phase I trial received a single i.v. injection of 223Ra. Five patients were included at each of the dosages: 46, 93, 163, 213, or 250 kBq/kg and followed for 8 weeks. Palliative response was evaluated according to the pain scale of the European Organization for Research and Treatment of Cancer QLQ C30 questionnaire at baseline and at 1, 4, and 8 weeks after injection.
Results: Weekly blood sampling during follow-up revealed mild and reversible myelosuppression with nadir 2 to 4 weeks after the injection. Importantly, for thrombocytes only grade 1 toxicity was reported. Grade 3 neutropenia and leucopenia occurred in two and three patients, respectively. Mild, transient diarrhea was observed in 10 of the 25 patients. Nausea and vomiting was more frequently observed in the highest dosage group. Serum alkaline phosphatase decreased with nadir averages of 29.5% in females and 52.1% in males. Pain relief was reported by 52%, 60%, and 56% of the patients after 7 days, 4, and 8 weeks, respectively. 223Ra cleared rapidly from blood and was below 1% of initial level at 24 hours. Gamma camera images indicated, in accordance with pretreatment 99mTc-MDP scans, accumulation of 223Ra in skeletal lesions. Elimination was mainly intestinal. Median survival exceeded 20 months.
Conclusions: 223Ra was well tolerated at therapeutically relevant dosages. Phase II studies have therefore been initiated.
Marimastat in the Treatment of Patients with Biochemically Relapsed Prostate Cancer: A Prospective Randomized, Double-Blind, Phase I/II Trial
Authors: Rosenbaum Eli , Zahurak Marianna , Sinibaldi Victoria , Carducci Michael A. , Pili Roberto , Laufer Menachem , DeWeese Theodore L. , Eisenberger Mario A. 
Published: September 2005

Abstract
Purpose: To evaluate the safety and biological activity of three different doses of marimastat given for 6 months to patients with biochemically relapsed prostate cancer.
Experimental Design: Patients with a biochemical relapse within 2 years of primary therapy, a prostate-specific antigen (PSA) increase of at least 50% within 6 months of study entry, and no prior systemic therapy were eligible. Patients were randomized to receive marimastat at total daily doses of 5, 20, or 40 mg for 6 months unless dose-limiting toxicity or new evidence of disease occurred.
Results: Thirty-nine patients were treated. Grade 3-4 reversible musculoskeletal toxicity was the only dose-limiting toxicity. Increasing dose was associated with increased probability of experiencing dose-limiting toxicity (5.9%, 42.9% and 88.9% for the 5, 20, and 40 mg groups, respectively; P = 0.03). Accrual was discontinued early on the two higher dose levels due to toxicity. A significant decrease in PSA slope was shown in the 20 mg group when compared with the 5 mg group (0.117 and −0.0046, respectively; P = 0.03) The 40 mg group (versus the 5 mg group) showed a similar change (0.109) with a trend towards significance (P = 0.07). An increased serum matrix metalloproteinase 2 level at month 3 compared with the baseline correlated with a decrease in PSA slopes (Slope, 0.001; 95% confidence interval, 0.0002-0.0018; P = 0.02).
Conclusion: These data suggest that marimastat has a biological effect and may effectively delay progression in patients with biochemical relapsed prostate cancer, as shown by the change in PSA slope; however, dose-limiting toxicity at active doses is significant. Confirmatory studies with less toxic matrix metalloproteinase inhibitors employing more conventional end points are indicated. This design is feasible and potentially efficient for screening antimetastatic agents.
WOX1 Is Essential for UVB Irradiation–Induced Apoptosis and Down-Regulated via Translational Blockade in UVB-Induced Cutaneous Squamous Cell Carcinoma In vivo
Authors: Lai Feng-Jie , Cheng Ching-Li , Chen Shur-Tzu , Wu Chin-Han , Hsu Li-Jin , Lee J. Yu-Yun , Chao Sheau-Chiou , Sheen Maw-Chang , Shen Ching-Liang , Chang Nan-Shan , Sheu Hamm-Ming 
Published: September 2005

Abstract
Purpose: We investigated the role of candidate tumor suppressor and proapoptotic WOX1 (also named WWOX, FOR, or WWOXv1) in UVB-induced apoptosis and formation of cutaneous squamous cell carcinomas (SCC).
Experimental Design: Expression of WOX1 and family proteins (WWOX) in human primary cutaneous SCCs was examined by immunohistochemistry, in situ hybridization, and reverse transcription-PCR. UVB irradiation–induced WOX1 activation (Tyr33 phosphorylation and nuclear translocation), apoptosis, and cutaneous SCC formation were examined both in vitro and in vivo.
Results: Up-regulation of human WOX1, isoform WOX2, and Tyr33 phosphorylation occurred during normal keratinocyte differentiation before cornification and death. Interestingly, significant reduction of these proteins and Tyr33 phosphorylation was observed in nonmetastatic and metastatic cutaneous SCCs (P &lt; 0.001), but without down-regulation of WWOX mRNA (P &gt; 0.05 versus normal controls), indicating a translational blockade of WWOX mRNA to protein. During acute exposure of hairless mice to UVB, WOX1 was up-regulated and activated in epidermal cells in 24 hours. In parallel with the clinical findings in humans, chronic UVB-treated mice developed cutaneous SCCs in 3 months, with significant reduction of WOX1 and Tyr33 phosphorylation and, again, without down-regulation of WWOX mRNA. Human SCC-25 and HaCaT cells were transfected with small interfering RNA–targeting WOX1 and shown to resist UVB-induced WOX1 expression, activation, and apoptosis.
Conclusions: WOX1 is essential for UVB-induced apoptosis and likely to be involved in the terminal differentiation of normal keratinocytes. During UVB-induced cutaneous SCC, epidermal cells have apparently prevented the apoptotic pressure from overexpressed WOX1 by shutting down the translation machinery for WWOX mRNA.
Down-Regulated Xanthine Oxidoreductase Is a Feature of Aggressive Breast Cancer
Authors: Linder Nina , Lundin Johan , Isola Jorma , Lundin Mikael , Raivio Kari O. , Joensuu Heikki 
Published: September 2005

AbstractPurpose: Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA, and high-energy phosphates and also plays a role in milk lipid globule secretion. Given the strong and regulated expression of XOR in normal breast epithelium, and the previously shown alterations of its expression in experimental tumorigenesis, we hypothesized that XOR may be differentially expressed in breast cancer.Experimental Design: XOR expression was analyzed by immunohistochemistry in tissue microarray specimens of 1,262 breast cancer patients with a median follow-up of 9.5 years.Results: Expression of XOR was moderately decreased in 50% and undetectable in another 7% of the tumors. Decreased XOR expression was associated with poor histologic grade of differentiation, ductal and lobular histologic types, large tumor size, high number of positive axillary lymph nodes, and high cyclooxygenase-2 expression, but not with estrogen or progesterone receptor status, Ki-67, p53, or ERBB2 amplification. Absence of XOR expression was associated with unfavorable outcome, and patients with no XOR expression had more than twice the risk of distant recurrence as compared with those with a moderately decreased or normal expression (hazard ratio, 2.21; P &lt; 0.0001). This was also true in patients with node-negative disease (hazard ratio, 2.75; P &lt; 0.0001) as well as in patients with small (≤1 cm) tumors (hazard ratio, 3.09; P = 0.027). In a multivariate survival analysis, negative XOR emerged as an independent prognostic factor both in the entire series (P = 0.01) and among patients with node-negative disease (P = 0.0009).Conclusion: Loss of XOR identifies breast cancer patients with unfavorable prognosis.
Clinical Significance of Human Kallikrein Gene 6 Messenger RNA Expression in Colorectal Cancer
Authors: Ogawa Kazuhiko , Utsunomiya Tohru , Mimori Koshi , Tanaka Fumiaki , Inoue Hiroshi , Nagahara Hisashi , Murayama Sadayuki , Mori Masaki 
Published: September 2005

Abstract
Purpose: Human kallikrein gene 6 (KLK6) is a member of the human kallikrein gene family, and recent studies have found that many kallikreins have altered expression patterns in various malignancies. The purpose of the current study was to quantify the expression of KLK6 in malignant and benign colorectal tissues and to statistically analyze whether KLK6 expression levels correlate with clinicopathologic variables and prognosis in patients with colorectal cancer.
Experimental Designs: Paired colorectal tissue samples from cancerous and corresponding noncancerous tissues were obtained from 63 patients with colorectal cancer who underwent surgical resection. Quantitative analyses of KLK6 mRNA expression were done using real-time quantitative reverse transcription-PCR.
Results: KLK6 mRNA overexpression in cancerous tissues compared with normal counterparts was observed in 57 of 63 (90%) patients. The mean expression level of KLK6 mRNA in cancerous tissues was significantly higher than that in noncancerous tissues (P &lt; 0.0001). Elevated KLK6 expression was significantly correlated with serosal invasion (P &lt; 0.05), liver metastasis (P &lt; 0.05), and advanced Duke's stage (P &lt; 0.01). Furthermore, patients with high KLK6 expression had a significantly poorer actuarial overall survival than patients with low KLK6 expression (5-year overall survival rates: 54% and 73%, respectively, P &lt; 0.05).
Conclusions: The results of this study indicated that KLK6 mRNA expression was significantly higher in cancerous than in noncancerous colorectal tissues, and high expression of KLK6 mRNA correlated with serosal invasion, liver metastasis, advanced Duke's stage, and a poor prognosis for patients with colorectal cancer.
Increased Estrogen Receptor βcx Expression during Mammary Carcinogenesis
Authors: Esslimani-Sahla Majida , Kramar Andrew , Simony-Lafontaine Joelle , Warner Margaret , Gustafsson Jan-Åke , Rochefort Henri 
Published: September 2005

Abstract
Identification of proteins that markedly vary during early steps of mammary carcinogenesis may help to understand its pathophysiology and to develop a prevention strategy. The expression of total estrogen receptor β (ERβ) protein and of its COOH-terminally spliced variant ERβcx (or ERβ2) was compared in 43 invasive breast cancers and in 39 adjacent normal mammary glands and 26 ductal carcinoma in situ (DCIS). Thirty-six breast cancers were ER positive by radioligand binding assay. The analysis was done by immunohistochemistry on adjacent sections of formalin-fixed, paraffin-embedded tumors using polyclonal anti-ERβ 503 IgY and sheep polyclonal ERβcx antibodies that were previously validated. Nuclear staining was quantified using a computerized image analyzer in selected areas of normal and cancer epithelial cells. Total ERβ expression was high in normal glands, decreased in DCIS (P = 0.0004), and increased from DCIS to invasive tumors (P = 0.029). In contrast, the ERβcx expression was low in normal glands, increased significantly in DCIS (P = 0.0014), and continued to increase in invasive carcinomas (P = 0.0027) in both ERα-positive and ERα-negative tumors. This is the first study showing a significant increase of the ERβcx variant protein in DCIS and invasive breast cancer compared with adjacent normal glands. This contrasts with the decrease of the total ERβ level in the same patients and indicates different mechanisms to explain these variations during mammary carcinogenesis. It also suggests a role of the ERβcx variant in carcinogenesis opposite to the protective effect of the wild-type ERβ1.
A Phase I Trial of Humanized Monoclonal Antibody A33 in Patients with Colorectal Carcinoma: Biodistribution, Pharmacokinetics, and Quantitative Tumor Uptake
Authors: Scott Andrew M. , Lee Fook-Thean , Jones Robert , Hopkins Wendie , MacGregor Duncan , Cebon Jonathan S. , Hannah Anthony , Chong Geoffrey , U Paul , Papenfuss Anthony , Rigopoulos Angela , Sturrock Susan , Murphy Roger , Wirth Veronika , Murone Carmel , Smyth Fiona E. , Knight Simon , Welt Sydney , Ritter Gerd , Richards Elizabeth , Nice Edouard C. , Burgess Antony W. , Old Lloyd J. 
Published: September 2005

Abstract
Purpose: To determine the in vivo characteristics of huA33, a CDR-grafted humanized antibody against the A33 antigen, we have conducted an open-label, dose escalation, biopsy-based phase I trial of huA33 in patients with colorectal carcinoma.
Experimental Design: Patients with colorectal carcinoma were infused with [131I]huA33 (400 MBq: 10 mCi) and [125I]huA33 (40 MBq: 1 mCi) 1 week before surgery. There were four huA33 dose levels (0.25, 1.0, 5.0, and 10 mg/m2). Adverse events, pharmacokinetics, biodistribution, tumor biopsies, and immune responses to huA33 were evaluated.
Results: There were 12 patients entered into the trial (6 males and 6 females; age range, 39-66 years). No dose-limiting toxicity was observed. The biodistribution of huA33 showed excellent uptake of [131I]huA33 in metastatic colorectal carcinoma. Pharmacokinetic analysis showed no significant difference in terminal half-life (T1/2β) between dose levels (mean ± SD, 86.92 ± 22.12 hours). Modeling of colon uptake of huA33 showed a T1/2 of elimination of 32.4 ± 8.1 hours. Quantitative tumor uptake ranged from 2.1 × 10−3 to 11.1 × 10−3 %ID/g, and tumor/normal tissue and tumor/serum ratios reached as high as 16.3:1 and 4.5:1, respectively. Biosensor analysis detected low-level human anti-human antibody responses in four patients following huA33 infusion.
Conclusions: huA33 shows selective and rapid localization to colorectal carcinoma in vivo and penetrates to the center of large necrotic tumors, and colon elimination half-life of huA33 is equivalent to basal colonocyte turnover. The excellent targeting characteristics of this humanized antibody indicate potential for the targeted therapy of metastatic colorectal cancer in future trials.