bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimetastatic Effect of an Orally Active Heparin Derivative on Experimentally Induced Metastasis
Authors: Lee Dong Yun , Park Kyeongsoon , Kim Sang Kyoon , Park Rang-Woon , Kwon Ick Chan , Kim Sang Yoon , Byun Youngro 
Published: May 2008

AbstractPurpose: Orally active anticancer drugs have great advantages for the treatment of cancer. Compelling data suggest that heparin exhibits critical antimetastatic effects via interference with P-selectin–mediated cell-cell binding. However, heparin should be given parenterally because it is not orally absorbed. Here, we evaluated the inhibitory effect of orally absorbable heparin derivative (LHD) on experimentally induced metastasis.Experimental Design: We developed LHD, which is a chemical conjugate of low molecular weight heparin and deoxycholic acid, and measured the plasma concentration of LHD after oral administration. To evaluate the antimetastatic effect of LHD, we carried out experimental lung metastasis assays in vivo using murine melanoma or human lung carcinoma cells and interruption assay between murine melanoma cells and activated platelets and human umbilical vascular endothelial cells in vitro.Results: In mice, the plasma concentration was ∼7 μg/mL at 20 minutes after oral administration of LHD (10 mg/kg), indicating that bleeding was not induced at this dose. Interestingly, we found that LHD dramatically attenuated metastasis experimentally induced by murine melanoma or human lung carcinoma cells and that its antimetastatic activity was attributed to the interruption of the interactions between melanoma cells and activated platelets and between melanoma cells and human umbilical vascular endothelial cells by blocking selectin-mediated interactions. Furthermore, it prevented tumor growth in secondary organs.Conclusions: On the basis of these findings, the present study shows the possibility of LHD as a suitable first-line anticancer drug that can be used for preventing metastasis and recurrence because it has therapeutic potential as an antimetastatic drug, has lower side effects, and can be orally absorbed.
Mature miR-184 as Potential Oncogenic microRNA of Squamous Cell Carcinoma of Tongue
Authors: Wong Thian-Sze , Liu Xiao-Bing , Wong Birgitta Yee-Hang , Ng Raymond Wai-Man , Yuen Anthony Po-Wing , Wei William Ignace 
Published: May 2008

Abstract
Purpose: The aim of this study was to evaluate the microRNA expression patterns in squamous cell carcinoma (SCC) of the tongue.
Experimental Design: Expression levels of 156 human mature microRNAs were examined using real-time quantitative PCR (Taq Man MicroRNA Assays; Human Panel) on laser microdissected cells of 4 tongue carcinomas and paired normal tissues. Expression of mature miR-184 was further validated in 20 paired tongue SCC and the normal tissues. Potential oncogenic functions of miR-184 were evaluated in tongue SCC cell lines (Cal27, HN21B, and HN96) with miR-184 inhibitor. Plasma miR-184 levels were evaluated using real-time quantitative PCR.
Results: Using 3-fold expression difference as a cutoff level, we identified 24 up-regulated mature miRNAs including miR-184, miR-34c, miR-137, miR-372, miR-124a, miR-21, miR-124b, miR-31, miR-128a, miR-34b, miR-154, miR-197, miR-132, miR-147, miR-325, miR-181c, miR-198, miR-155, miR-30a-3p, miR-338, miR-17-5p, miR-104, miR-134, and miR-213; and 13 down-regulated mature miRNAs including miR-133a, miR-99a, miR-194, miR-133b, miR-219, miR-100, miR-125b, miR-26b, miR-138, miR-149, miR-195, miR-107, and miR-139. Overexpression of miR-184 was further validated in 20 paired tongue SCC and normal tissues (P = 0.002). Inhibition of miR-184 in tongue SCC cell lines could reduce cell proliferation rate. Down-regulation of c-Myc was observed in two cell lines in response to miR-184 inhibitor. Suppressing miR-184 could induce apoptosis in all three cell lines. Plasma miR-184 levels were significantly higher in tongue SCC patients in comparison with normal individuals, and the levels were significantly reduced after surgical removal of the primary tumors.
Conclusions: Overexpression of miR-184 might play an oncogenic role in the antiapoptotic and proliferative processes of tongue SCC. In addition, plasma miR-184 levels were associated with the presence of primary tumor. Further studies on the aberrantly expressed miRNAs in tongue SCC as well as using plasma miRNAs as novel tumor markers are warranted.
Treatment of Hormone-Refractory Prostate Cancer with Docetaxel or Mitoxantrone: Relationships between Prostate-Specific Antigen, Pain, and Quality of Life Response and Survival in the TAX-327 Study
Authors: Berthold Dominik R. , Pond Gregory R. , Roessner Martin , de Wit Ronald , Eisenberger Mario , Tannock and Ian F. ,   on behalf of the TAX-327 investigators
Published: May 2008

Abstract
Purpose: The TAX-327 study randomized 1,006 men with metastatic hormone-refractory prostate cancer to receive 3-weekly docetaxel, weekly docetaxel, or mitoxantrone, each with prednisone.
Experimental Design: We used the TAX-327 database to address (a) the relationship between quality of life (QoL) and pain; (b) whether minimally symptomatic patients benefit from treatment or have treatment-related decline in QoL; (c) the relationships between prostate-specific antigen (PSA) response, pain response, and QoL response; (d) the times at which these responses are first observed; and (e) whether PSA, pain, and/or QoL response predict for overall survival.
Results: At baseline, 374 of 815 men assessed for QoL had major pain; of these, 92% had substantial impairment of QoL compared with 75% without major pain (P &lt; 0.001). Men with minimal symptoms had prolonged survival (median, 25.6 months) compared with symptomatic patients (median, 17.1 months; P = 0.009); they were more likely to have initial deterioration of QoL if treated with weekly docetaxel. PSA response and pain response, but not QoL response, were independently associated with survival in landmark analysis. Median times to PSA and pain response were 44 and 27 days, respectively; some men had initial increase in serum PSA before subsequent decline.
Conclusions: Symptoms other than pain contribute to impaired QoL in men with hormone-refractory prostate cancer. Those with minimal symptoms have prolonged survival. Both pain and PSA response are associated with survival but are not adequate to use as surrogate end points in phase 3 studies. Early increases in serum PSA (up to 12 weeks) should be ignored when determining response or progression.
Down-Regulation of Phosphatidylinositol 3′-Kinase/AKT/Molecular Target of Rapamycin Metabolic Pathway by Primary Letrozole-Based Therapy in Human Breast Cancer
Authors: Generali Daniele , Fox Stephen B. , Brizzi Maria Pia , Allevi Giovanni , Bonardi Simone , Aguggini Sergio , Milani Manuela , Bersiga Alessandra , Campo Leticia , Dionisio Rossana , Vergoni Federica , Giardini Roberto , Dogliotti Luigi , Bottini Alberto , Harris Adrian L. , Berruti Alfredo 
Published: May 2008

Abstract
Purpose: The phosphatidylinositol 3′-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway is involved in the development of tumor resistance to endocrine therapy in breast cancer cell lines and represents an attractive target for pharmacologic intervention. However, the effects of endocrine therapy with aromatase inhibitors on in vivo expression of this signaling cascade, and its relation to tumor response and patient outcome, is unknown.
Experimental Design: PI3K, phospho-AKT (pAKT) and phospho-mTOR were assessed by immunohistochemistry on tumor specimens collected at baseline and after 6 months of treatment in 113 elderly breast cancer patients consecutively enrolled in a randomized phase II trial of primary letrozole therapy and letrozole associated with metronomic cyclophosphamide.
Results: Basal expression of the pathway was not significantly correlated with response or patient outcome. Both letrozole alone and letrozole with cyclophosphamide resulted in a significant reduction of PI3K expression (P = 0.02 and P &lt; 0.005, respectively) and phospho-mTOR expression (P = 0.0001 and P = 0.0001, respectively). pAKT showed no change in the letrozole arm, whereas it was significantly decreased in the letrozole plus cyclophosphamide arm (P &lt; 0.005). pAKT expression reduction was associated with a greater response rate (P = 0.05) and greater reduction in Ki67 expression (P = 0.05). Phospho-mTOR expression reduction was associated with a significantly longer disease-free survival in a multivariate analysis (P = 0.02).
Conclusions: Letrozole inhibits key molecules in the PI3K pathway that are important targets of new drugs being developed to overcome resistance. Changes in these molecules may have prognostic significance. These results should be taken into account when planning prospective trials testing up-front aromatase inhibitor with drugs targeting the PI3K/AKT/mTOR signaling pathway.
Altered MicroRNA Expression in Cervical Carcinomas
Authors: Lee Jeong-Won , Choi Chel Hun , Choi Jung-Joo , Park Young-Ae , Kim Seung-Jun , Hwang Seung Yong , Kim Woo Young , Kim Tae-Joong , Lee Je-Ho , Kim Byoung-Gie , Bae Duk-Soo 
Published: May 2008

Abstract
Purpose: MicroRNAs (miRNA) are small noncoding RNAs that are 18 to 25 nucleotides in length; they regulate the stability or translational efficiency of target mRNAs. Emerging evidence suggests that miRNAs might be involved in the pathogenesis of a variety of human cancers.
Experimental Design: In this study, we profiled miRNA expression in 10 early stage invasive squamous cell carcinomas (ISCC) and 10 normal cervical squamous epithelial specimens using TaqMan real-time quantitative PCR array methods. In order to evaluate the role of miR-199a, one of the most significantly overexpressed in ISCCs, we transfected cervical cancer cells (SiHa and ME-180) with anti–miR-199a oligonucleotides and assessed the cell viability.
Results: We found 70 genes (68 up-regulated, 2 down-regulated) with significantly different expression in the ISCCs compared with normal samples (P &lt; 0.05). When we analyzed the expression of the 10 most significant miRNAs in 31 ISCCs, increased miR-127 expression was significantly associated with lymph node metastasis (P = 0.006). Transfection of anti–miR-199a oligonucleotides to cervical cancer cells suppressed cell growth in vitro, which was potentiated with the anticancer agent cisplatin.
Conclusions: Our results show that miRNA deregulation may play an important role in the malignant transformation of cervical squamous cells. In addition, they may offer new candidate targets to be exploited for both prognostic and therapeutic strategies in patients with cervical cancer.
Quantitative Promoter Hypermethylation Analysis of Cancer-Related Genes in Salivary Gland Carcinomas: Comparison with Methylation-Specific PCR Technique and Clinical Significance
Authors: Lee Eung-Seok , Issa Jean-Pierre , Roberts Dianna B. , Williams Michelle D. , Weber Randal S. , Kies Merrill S. , El-Naggar Adel K. 
Published: May 2008

AbstractPurpose: To compare the methylation status of tumor-associated genes by quantitative pyrosequencing and qualitative methylation-specific PCR (MSP) techniques and to correlate the results with clinicopathologic features and patients outcome to determine which method might have greater clinical utility.Experimental Design: The hypermethylation status of the retinoid acid receptor β2 (RARβ2), RAS association domain family 1A (RASSF1A), O6-methylguanine-DNA methyltransferase (MGMT), and E-cadherin genes was analyzed in five salivary carcinoma cell lines and 69 human salivary gland carcinoma specimens by pyrosequencing and MSP techniques. The two datasets were compared by linear regression. Correlations between methods and with clinicopathologic characteristics were assessed by Pearson's χ2 test or the two-tailed Fisher exact test, as applicable, using cutoff points determined from the regression curves and empirical fitting. We also investigated the effect of demethylating agents on methylated genes in cell lines to assess their effect on the expression of these genes.Results: Overall, regression analysis indicated high degrees of correlation of the two methods for measurement of methylation for the RARb2, RASSF1A, and MGMT genes (adjusted R2 = 0.319, 0.835, and 0.178; P &lt; 0.001, &lt;0.001, and 0.0002, respectively) among the 69 tumors tested. However, the pyrosequencing technique yielded four more instances of methylation above background levels than MSP for RARβ2 and three more for RASSF1. Methylation of either RARβ2 and RASSF1A alone or both by pyrosequencing were correlated with tumor type (P = 0.027, 0.014, and 0.012, respectively). Methylation of RARβ2 alone and in combination with RASSF1A by pyrosequencing were also significantly correlated with tumor grade (P = 0.014 and 0.011, respectively) and 3-year survival (P = 0.002 and 0.004, respectively). The survival curves of patients who had hypermethylation at both RARβ2 and RASSF1A were significantly lower than those of patients who had hypermethylation at neither or just for the RASSF1A (P = 0.008 and 0.007, respectively). 5-Azadeoxycytidine treatment of methylated cell lines led to the reactivation of RARβ2 expression in only one of the five cell lines.Conclusions: (a) Although the methylation status of RARb2, RASSF1A, and MGMT genes by both techniques were significantly correlated, pyrosequencing is generally more sensitive and its results correlate better with the clinical variables than those of MSP. (b) The methylation level of the RARβ2 and/or RASSF1A by pyrosequencing is significantly associated with aggressive tumor phenotypes and patients survival.
The Effects of Neoadjuvant Anastrozole and Tamoxifen on Circulating Vascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor Receptor 1 in Breast Cancer
Authors: Banerjee Susana , Pancholi Sunil , A'Hern Roger , Ghazoui Zara , Smith Ian E. , Dowsett Mitch , Martin Lesley-Ann 
Published: May 2008

Abstract
Purpose: Vascular endothelial growth factor (VEGF) is a key angiogenic factor mediating neovascularization. Soluble VEGF receptor 1 (sVEGFR-1) is an intrinsic negative counterpart of VEGF signaling and the ratio of sVEGFR-1 to VEGF has been shown to be a prognostic factor. Estrogen-bound estrogen receptor enhances VEGF expression, providing a common link between these signaling pathways that may be targeted by endocrine therapy. We investigated the effects of anastrozole and tamoxifen over time on serum VEGF and sVEGFR-1.
Experimental Design: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial compared the preoperative use of anastrozole with tamoxifen in postmenopausal women with estrogen receptor–positive primary operable breast cancer over 12 weeks. Circulating VEGF and sVEGFR-1 were measured by ELISA in 106 patients treated with anastrozole or tamoxifen alone at baseline and after 2 and 12 weeks of treatment.
Results: The increase in serum VEGF from baseline to 12 weeks was significantly different between anastrozole and tamoxifen (anastrozole versus tamoxifen, 6% versus 38%; P = 0.047). There was a significant increase in sVEGFR-1 levels after 12 weeks of anastrozole (P = 0.037). The sVEGFR-1/VEGF ratio significantly decreased in the tamoxifen arm (P = 0.013) and the change in sVEGFR-1/VEGF ratio from baseline to 12 weeks was significantly different between anastrozole and tamoxifen (anastrozole versus tamoxifen, 24% increase versus 34% decrease; P = 0.013).
Conclusions: Treatment with anastrozole and tamoxifen resulted in differential effects on serum angiogenic markers. This may be related to the relative effectiveness of the treatments. These data provide further support for cross talk between estrogen receptor and VEGF.
Use of Yeast-SecretedIn vivoBiotinylated Recombinant Antibodies (Biobodies) in Bead-Based ELISA
Authors: Scholler Nathalie , Lowe Kimberly A. , Bergan Lindsay A. , Kampani Archana V. , Ng Vivian , Forrest Robin M. , Thorpe Jason D. , Gross Jenny A. , Garvik Barbara M. , Drapkin Ronny , Anderson Garnet L. , Urban Nicole 
Published: May 2008

AbstractPurpose: To measure circulating antigens, sandwich ELISA assays require two complementary affinity reagents. Mouse monoclonal antibodies (mAb) and polyclonal antibodies (pAb) are commonly used, but because their production is lengthy and costly, recombinant antibodies are emerging as an attractive alternative.Experimental Design: We developed a new class of recombinant antibodies called biobodies (Bb) and compared them to mAb for use in serodiagnosis. Bbs were secreted biotinylated in vivo by diploid yeast and used as affinity reagents after Ni purification. Bead-based assays for HE4 and mesothelin were developed using Bbs in combination with pAbs (Bb/pAb assays). To assess precision, reproducibility studies were done using four runs of 16 replicates at six analyte levels for each marker. Pearson correlations and receiver-operator characteristic analyses were done in 214 patient serum samples to directly compare the Bb/pAb assays to mAb assays. Diagnostic performance of the Bb/pAb assay was further assessed in an expanded set of 336 ovarian cancer cases and controls.Results: On average across analyte levels, Bb/pAb assays yielded within-run and between-run coefficients of variations of 11.7 and 23.8, respectively, for HE4 and 14.0 and 14.5, respectively, for mesothelin. In the subset (n = 214), Pearson correlations of 0.95 for HE4 and 0.92 for mesothelin were observed between mAb and Bb/pAb assays. The area under the curves for the mAb and Bb/pAb assays were not significantly different for HE4 (0.88 and 0.84, respectively; P = 0.20) or mesothelin (0.74 and 0.72, respectively; P = 0.38).Conclusion: Yeast-secreted Bbs can be used reliably in cost-effective yet highly sensitive bead–based assays for use in large validation studies.
A Phase I Pharmacokinetic and Pharmacodynamic Correlative Study of the Antisense Bcl-2 Oligonucleotide G3139, in Combination with Carboplatin and Paclitaxel, in Patients with Advanced Solid Tumors
Authors: Liu Glenn , Kolesar Jill , McNeel Douglas G. , Leith Catherine , Schell Kathy , Eickhoff Jens , Lee Fred , Traynor Anne , Marnocha Rebecca , Alberti Dona , Zwiebel James , Wilding George 
Published: May 2008

Abstract
Purpose: This phase I trial assessed the safety and tolerability of G3139 when given in combination with carboplatin and paclitaxel chemotherapy. The effect of G3139 treatment on Bcl-2 expression in peripheral blood mononuclear cells (PBMC) and paired tumor biopsies was also determined.
Experimental Design: Patients with advanced solid malignancies received various doses of G3139 (continuous i.v. infusion days 1-7), carboplatin (day 4), and paclitaxel (day 4), repeated in 3-week cycles, in a standard cohort-of-three dose-escalation schema. Changes in Bcl-2/Bax transcription/expression were assessed at baseline and day 4 (prechemotherapy) in both PBMCs and paired tumor biopsies. The pharmacokinetic interactions between G3139 and carboplatin/paclitaxel were measured.
Results: Forty-two patients were evaluable for safety analysis. Primary toxicities were hematologic (myelosuppression and thrombocytopenia). Dose escalation was stopped with G3139 at 7 mg/kg/d, carboplatin at area under the curve of 6, and paclitaxel at 175 mg/m2 due to significant neutropenia seen in cycle 1 and safety concerns in further escalating chemotherapy in this phase I population. With G3139 at 7 mg/kg/d, 13 patients underwent planned tumor biopsies, of which 12 matched pairs were obtained. Quantitative increases in intratumoral G3139 with decreases in intratumoral Bcl-2 gene expression were seen. This paralleled a decrease in Bcl-2 protein expression observed in PBMCs.
Conclusions: Although the maximal tolerated dose was not reached, the observed toxicities were consistent with what one would expect from carboplatin and paclitaxel alone. In addition, we show that achievable intratumoral G3139 concentrations can result in Bcl-2 down-regulation in solid tumors and PBMCs.
Treatment of Radioresistant Stem-Like Esophageal Cancer Cells by an Apoptotic Gene-Armed, Telomerase-Specific Oncolytic Adenovirus
Authors: Zhang Xiaochun , Komaki Ritsuko , Wang Li , Fang Bingliang , Chang Joe Y. 
Published: May 2008

Abstract
Purpose: Radioresistance may be caused by cancer stem cells (CSC). Because CSCs require telomerase to proliferate, a telomerase-specific oncolytic adenoviral vector carrying apoptotic tumor necrosis factor–related apoptosis-inducing ligand and E1A gene (Ad/TRAIL-E1) may preferentially target CSCs.
Experimental Design: We established two pairs of parental and radioresistant (R) esophageal carcinoma cell lines (Seg-1, Seg-1R and TE-2, TE-2R) by fractionated irradiation. Stem cell markers were measured by Western blotting and flow cytometry. Serial sorting was used to enrich stem-like side population cells. Telomerase activity, transgene expression, antitumor activity, apoptosis induction, and viral replication were determined in vitro and/or in vivo.
Results: Expression of the stem cell markers β-catenin, Oct3/4, and β1 integrin in Seg-1R cells was 29.4%, 27.5%, and 97.3%, respectively, compared with 4.8%, 14.9%, and 45.3% in Seg-1 cells (P &lt; 0.05). SP levels in Seg-1R and TE-2R cells were 14.6% and 2.7%, respectively, compared with 3.4% and 0.3% in Seg-1 and TE-2 cells. Serial sorting of Seg-1R SP cells showed enrichment of the SP cells. Telomerase activities in Seg-1R, Seg-1R SP, and TE-2R cells were significantly higher than in Seg-1, Seg-1R non-SP, and TE-2 cells, respectively (P &lt; 0.05). Seg-1R and TE-2R cells were more sensitive to Ad/TRAIL-E1 than parental cells. Increased Coxsackie-adenovirus receptor and elevated transgene expressions were found in the radioresistant cells. Ad/TRAIL-E1 resulted in significant tumor growth suppression and longer survival in Seg-1R–bearing mice (P &lt; 0.05) with no significant toxicity.
Conclusion: Radioresistant cells established by fractionated irradiation display CSC-like cell properties. Ad/TRAIL-E1 preferentially targets radioresistant CSC-like cells.