bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Paclitaxel-Hyaluronan Bioconjugate Targeting Ovarian Cancer Affords a Potent In vivo Therapeutic Activity
Authors: Banzato Alessandra , Bobisse Sara , Rondina Maria , Renier Davide , Bettella Fabio , Esposito Giovanni , Quintieri Luigi , Meléndez-Alafort Laura , Mazzi Ulderico , Zanovello Paola , Rosato Antonio 
Published: June 2008

Abstract
Purpose: This study was designed to evaluate the pharmacologic and biological properties of a paclitaxel-hyaluronan bioconjugate (ONCOFID-P) against IGROV-1 and OVCAR-3 human ovarian cancer xenografts following i.p. administration.
Experimental Design: In vitro tumor sensitivity to ONCOFID-P was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, whereas bioconjugate interaction with cells was studied cytofluorimetrically and by confocal microscopy. In vivo toxicity was assessed by a single-dose maximum-tolerated dose, peripheral blood cell count determination and by histologic analysis. Biodistribution of the compound was evaluated with a small animal–dedicated scintigraphy gamma camera following injection of 99mTc-labeled ONCOFID-P. Pharmacokinetic analysis was also carried out. Female severe combined immunodeficiency mice implanted with ovarian cancer cells underwent treatment with ONCOFID-P or free paclitaxel starting from day 7 or 14 after tumor injection, and survivals were compared.
Results: ONCOFID-P interacted with CD44, entered cells through a receptor-mediated mechanism, and exerted a concentration-dependent inhibitory effect against tumor cell growth. After i.p. administration, the bioconjugate distributed quite uniformly within the peritoneal cavity, was well-tolerated, and was not associated with local histologic toxicity. Pharmacokinetic studies revealed that blood levels of bioconjugate-derived paclitaxel were much higher and persisted longer than those obtained with the unconjugated free drug. Intraperitoneal treatment of tumor-bearing mice with the bioconjugate revealed that ONCOFID-P exerted a relevant increase in therapeutic activity compared with free drug.
Conclusions: ONCOFID-P significantly improved results obtained with conventional paclitaxel, in terms of in vivo tolerability and therapeutic efficacy; these data strongly support its development for locoregional treatment of ovarian cancer.
Nonviral Nanoscale-Based Delivery of Antisense Oligonucleotides Targeted to Hypoxia-Inducible Factor 1α Enhances the Efficacy of Chemotherapy in Drug-Resistant Tumor
Authors: Wang Yang , Saad Maha , Pakunlu Refika I. , Khandare Jayant J. , Garbuzenko Olga B. , Vetcher Alexandre A. , Soldatenkov Viatcheslav A. , Pozharov Vitaly P. , Minko Tamara 
Published: June 2008

Abstract
Purpose: To enhance the efficacy of cancer treatment, we propose a complex approach: simultaneous delivery to the tumor of a chemotherapeutic agent and a suppressor of hypoxia-inducible factor 1α (HIF1A).
Experimental Design: The novel complex liposomal drug delivery system was developed and evaluated in vitro and in vivo on nude mice bearing xenografts of multidrug-resistant human ovarian carcinoma. The proposed novel complex drug delivery system consists of liposomes as a nanocarrier, a traditional anticancer drug (doxorubicin) as a cell death inducer, and antisense oligonucleotides targeted to HIF1A mRNA as a suppressor of cellular resistance and angiogenesis.
Results: The system effectively delivers active ingredients into tumor cells, multiplies the cell death signal initiated by doxorubicin, and inhibits cellular defensive mechanisms and angiogenesis by down-regulating BCL2, HSP90, and vascular endothelial growth factor proteins. This, in turn, activates caspases, promotes apoptosis, necrosis, and tumor shrinkage. The proposed novel complex multipronged approach enhances the efficiency of chemotherapy.
Conclusions: The proposed combination therapy prevents the development of resistance in cancer cells, and thus, increases the efficacy of chemotherapy to an extent that cannot be achieved by individual components applied separately. It could form the foundation for a novel type of cancer therapy based on simultaneous delivery of an anticancer drug and a suppressor of HIF1A.
TMPRSS2:ERG Fusion Identifies a Subgroup of Prostate Cancers with a Favorable Prognosis
Authors: Saramäki Outi R. , Harjula Anna E. , Martikainen Paula M. , Vessella Robert L. , Tammela Teuvo L.J. , Visakorpi Tapio 
Published: June 2008

Abstract
Purpose: Our aim was to assess the frequency of ERG overexpression and TMPRSS2:ERG rearrangement in prostate cancer and their association with clinicopathologic variables and outcome.
Experimental Design: The presence of the TMPRSS2:ERG rearrangement was studied by reverse transcription-PCR and fluorescence in situ hybridization in 19 prostate cancer xenografts and 7 prostate cancer cell lines. The expression of ERG was studied in the xenografts and cell lines and in 49 freshly frozen clinical prostate samples by quantitative reverse transcription-PCR. The frequency of the TMPRSS2:ERG fusion in clinical prostate cancer (n = 253) on tissue microarrays was assessed by three-color fluorescence in situ hybridization.
Results: Seven of 19 (37%) of the xenografts overexpressed ERG and had TMPRSS2:ERG rearrangement. Two xenografts, representing small cell carcinomas, also contained the fusion but did not express ERG. In clinical tumor specimens, the overexpression of ERG was associated with the rearrangement (P = 0.0019). Fifty of 150 (33%) of the prostatectomy specimens and 28 of 76 (37%) of the hormone-refractory prostate cancers on the tissue microarrays carried the TMPRSS2:ERG rearrangement. It was associated with longer progression-free survival in patients treated by prostatectomy (P = 0.019), and according to multivariate analysis, it was an independent predictor of favorable outcome (relative risk, 0.54; 95% confidence interval, 0.30-0.98). The fusion was not associated with Gleason score, pT stage, diagnostic prostate-specific antigen, or cell proliferation activity in prostatectomy specimens nor with the AR gene amplification in hormone-refractory tumors.
Conclusions: The TMPRSS2:ERG rearrangement can be found in about one third of prostate cancers. A subgroup of prostate cancer patients with a good prognosis may be identified by the rearrangement.
Astrocyte Elevated Gene-1 is a Novel Prognostic Marker for Breast Cancer Progression and Overall Patient Survival
Authors: Li Jun , Zhang Nu , Song Li-Bing , Liao Wen-Ting , Jiang Li-Li , Gong Li-Yun , Wu Jueheng , Yuan Jie , Zhang Hui-Zhong , Zeng Mu-Sheng , Li Mengfeng 
Published: June 2008

Abstract
Purpose: The present study was aimed at clarifying the expression of astrocyte elevated gene-1 (AEG-1), one of the target genes of oncogenic Ha-ras, in breast cancer and its correlation with clinicopathologic features, including the survival of patients with breast cancer.
Experimental Design: The expression of AEG-1 in normal breast epithelial cells, breast cancer cell lines, and in four cases of paired primary breast tumor and normal breast tissue was examined using reverse transcription-PCR and Western blot. Real-time reverse transcription-PCR was applied to determine the mRNA level of AEG-1 in the four paired tissues, each from the same subject. Furthermore, AEG-1 protein expression was analyzed in 225 clinicopathologically characterized breast cancer cases using immunohistochemistry. Statistical analyses were applied to test for the prognostic and diagnostic associations.
Results: Western blot and reverse transcription-PCR showed that the expression level of AEG-1 was markedly higher in breast cancer cell lines than that in the normal breast epithelial cells at both mRNA and protein levels. AEG-1 expression levels were significantly up-regulated by up to 35-fold in primary breast tumors in comparison to the paired normal breast tissue from the same patient. Immunohistochemical analysis revealed high expression of AEG-1 in 100 of 225 (44.4%) paraffin-embedded archival breast cancer biopsies. Statistical analysis showed a significant correlation of AEG-1 expression with the clinical staging of the patients with breast cancer (P = 0.001), as well as with the tumor classification (P = 0.004), node classification (P = 0.026), and metastasis classification (P = 0.001). Patients with higher AEG-1 expression had shorter overall survival time, whereas patients with lower AEG-1 expression had better survival. Multivariate analysis suggested that AEG-1 expression might be an independent prognostic indicator for the survival of patients with breast cancer.
Conclusions: Our results suggest that AEG-1 protein is a valuable marker of breast cancer progression. High AEG-1 expression is associated with poor overall survival in patients with breast cancer.
Effect of SLCO1B3 Haplotype on Testosterone Transport and Clinical Outcome in Caucasian Patients with Androgen-Independent Prostatic Cancer
Authors: Hamada Akinobu , Sissung Tristan , Price Douglas K. , Danesi Romano , Chau Cindy H. , Sharifi Nima , Venzon David , Maeda Kenji , Nagao Keisuke , Sparreboom Alex , Mitsuya Hiroaki , Dahut William L. , Figg William D. 
Published: June 2008

Abstract
Purpose: The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. However, its role in testosterone uptake and clinical outcome of prostatic cancer is unknown. This study examined (a) the SLCO1B3 genotype in cancer cells as well as the uptake of testosterone by cells transfected with genetic variants of SLCO1B3; (b) the expression of OATP1B3 in normal prostate, benign prostatic hyperplasia, and prostatic cancer; and (c) the role of SLCO1B3 haplotype on clinical outcome of Caucasian patients with androgen-independent prostatic cancer.
Experimental Design: SLCO1B3 genotype was assessed in the NCI-60 panel of tumor cells by sequencing, whereas testosterone transport was analyzed in Cos-7 cells transfected with WT, 334G, and 699A SLCO1B3 variants. OATP1B3 expression in prostatic tissues was examined by fluorescence microscopy, and the relationship between SLCO1B3 haplotypes and survival was examined in patients.
Results: Cells transfected with wild-type (334T/699G) SLCO1B3, or with a vector containing either the 334G or 699A variants, actively transported testosterone, whereas its uptake was impaired in cells transfected with a gene carrying both 334G and 699A single nucleotide polymorphisms. Prostatic cancer overexpresses OATP1B3 compared with normal or benign hyperplastic tissue; patients with SLCO1B3 334GG/699AA haplotype showed longer median survival (8.5 versus 6.4 years; P = 0.020) and improved survival probability at 10 years (42% versus 23%; P &lt; 0.023) than patients carrying TT/AA and TG/GA haplotypes.
Conclusions: The common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with prostatic cancer.
Combination Strategy Targeting the Hypoxia Inducible Factor-1α with Mammalian Target of Rapamycin and Histone Deacetylase Inhibitors
Authors: Verheul Henk M.W. , Salumbides Brenda , Van Erp Karen , Hammers Hans , Qian David Z. , Sanni Tolib , Atadja Peter , Pili Roberto 
Published: June 2008

Abstract
Purpose: The hypoxia-inducible factor-1α (HIF-α) is a key regulator of tumor angiogenesis. Mammalian target of rapamycin (mTOR) and histone deacetylase (HDAC) inhibitors suppress tumor-induced angiogenesis by reducing tumor HIF-1α protein expression. Thus, we hypothesized that combination treatment of rapamycin and the HDAC inhibitor LBH589 has greater antiangiogenic and antitumor activity compared with single agents.
Experimental Design: To evaluate the effect of LBH589 and rapamycin on HIF-1α in human prostate PC3, renal C2 carcinoma cell lines, and endothelial cells (human umbilical vein endothelial cells), we did Western blot analysis. To determine the antitumor activity of LBH589 and rapamycin, cell proliferation assays and xenograft experiments were conducted.
Results: Western blotting showed that combination treatment of human umbilical vein endothelial cells, C2 and PC3, significantly reduced HIF-1α protein expression compared with single agents. Treatment with rapamycin resulted in inhibition of the downstream signals of the mTOR pathway and increased phosphorylation of Akt in C2 cells, whereas the constitutively activated Akt in PC3 cells was not modulated. LBH589 decreased both constitutively expressed and rapamycin-induced phosphorylated Akt levels in PC3 and C2 cell lines. In clonogenic assays, the combination treatment had a greater inhibitory effect in PC3 cells (93 ± 1.4%) compared with single agents (66 ± 9% rapamycin and 43 ± 4% LBH589). Combination of rapamycin and LBH589 significantly inhibited PC3 and C2 in vivo tumor growth and angiogenesis as measured by tumor weight and microvessel density.
Conclusions: Combination treatment of mTOR and HDAC inhibitors represents a rational therapeutic strategy targeting HIF-1α that warrants clinical testing.
HLA Class I Antigen Processing Machinery Component Expression and Intratumoral T-Cell Infiltrate as Independent Prognostic Markers in Ovarian Carcinoma
Authors: Han Liz Y. , Fletcher Mavis S. , Urbauer Diana L. , Mueller Peter , Landen Charles N. , Kamat Aparna A. , Lin Yvonne G. , Merritt William M. , Spannuth Whitney A. , Deavers Michael T. , De Geest Koen , Gershenson David M. , Lutgendorf Susan K. , Ferrone Soldano , Sood Anil K. 
Published: June 2008

AbstractPurpose: Defects in the antigen processing machinery (APM) may provide tumor cells with a mechanism to escape immune recognition. The purpose of this study is to determine the clinical significance of APM component down-regulation and tumor-infiltrating T cells in ovarian carcinoma.Experimental Design: After institutional review board approval, tumor samples from 150 patients with invasive epithelial ovarian cancers were examined for TAP1, TAP2, tapasin, HLA class I heavy chain (HLA-HC), β2 microglobulin, and T-cell (CD3+ and CD8+) tumor infiltration using immunohistochemistry.Results: The majority of tumors had either heterogeneous or positive expression of TAP1, TAP2, HLA-HC, and β2 microglobulin (66.7%, 73.3%, 70.7%, and 63.3%, respectively), except tapasin for which 58% of the tumors lacked expression. Furthermore, 67% and 88% of the lesions possessed intratumoral and peritumoral CD3+ or CD8+ cells, respectively. The majority of APM component expression examined was significantly associated with both intratumoral and peritumoral T-cell infiltration (P &lt; 0.05). The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival (all P ≤ 0.01); however, peritumoral T-cell infiltrates did not significantly affect survival (P = 0.33). APM component down-regulation (P &lt; 0.001), lack of intratumoral T-cell infiltrates (P = 0.03), and suboptimal cytoreduction (P &lt; 0.001) were independent prognostic markers for death from ovarian carcinoma.Conclusion: The negative effect of APM component down-regulation by itself and in combination with absent intratumoral T-cell infiltration on the survival of patients with ovarian carcinoma implies a role for immune escape in addition to immunosurveillance in the clinical course of disease.
Oral Administration of Gemcitabine in Patients with Refractory Tumors: A Clinical and Pharmacologic Study
Authors: Veltkamp Stephan A. , Jansen Robert S. , Callies Sophie , Pluim Dick , Visseren-Grul Carla M. , Rosing Hilde , Kloeker-Rhoades Susanne , Andre Valerie A.M. , Beijnen Jos H. , Slapak Christopher A. , Schellens Jan H.M. 
Published: June 2008

Abstract
Purpose: To determine the toxicity, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of oral gemcitabine (2′,2′-difluorodeoxycytidine; dFdC) in patients with cancer.
Experimental Design: Patients with advanced or metastatic cancer refractory to standard therapy were eligible. Gemcitabine was administered p.o. starting at 1 mg once daily using dose escalation with three patients per dose level. Patients received one of two dosing schemes: (a) once daily dosing for 14 days of a 21-day cycle or (b) every other day dosing for 21 days of a 28-day cycle. Pharmacokinetics were assessed by measuring concentrations of dFdC and 2′,2′-difluorodeoxyuridine (dFdU) in plasma and gemcitabine triphosphate in peripheral blood mononuclear cells, and pharmacodynamics by measuring the effect on T-cell proliferation.
Results: Thirty patients entered the study. Oral gemcitabine was generally well-tolerated. The maximum tolerated dose was not reached. Mainly moderate gastrointestinal toxicities occurred except for one patient who died after experiencing grade 4 hepatic failure during cycle two. One patient with a leiomyosarcoma had stable disease during 2 years and 7 months. Systemic exposure to dFdC was low with an estimated bioavailability of 10%. dFdC was highly converted to dFdU, probably via first pass metabolism and dFdU had a long terminal half-life (∼89 h). Concentrations of dFdCTP in peripheral blood mononuclear cells were low, but high levels of gemcitabine triphosphate, the phosphorylated metabolite of dFdU, were detected.
Conclusions: Systemic exposure to oral gemcitabine was low due to extensive first-pass metabolism to dFdU. Moderate toxicity combined with hints of activity warrant further investigation of the concept of prolonged exposure to gemcitabine.
Aneuploidy Predicts Outcome in Patients with Endometrial Carcinoma and Is Related to Lack of CDH13 Hypermethylation
Authors: Suehiro Yutaka , Okada Toshiyuki , Okada Takae , Anno Keiko , Okayama Naoko , Ueno Koji , Hiura Mikako , Nakamura Mikiko , Kondo Tomoko , Oga Atsunori , Kawauchi Shigeto , Hirabayashi Kei , Numa Fumitaka , Ito Takehisa , Saito Toshiaki , Sasaki Kohsuke , Hinoda Yuji 
Published: June 2008

Abstract
Purpose: Many investigators have reported that aneuploidy detected by flow cytometry is a useful prognostic marker in patients with endometrial cancer. Laser scanning cytometry (LSC) is a technology similar to flow cytometry but is more feasible for clinical laboratory use. We evaluated the usefulness of DNA ploidy detected by LSC as a prognostic marker in patients with endometrial cancer and investigated genetic and epigenetic factors related to aneuploidy.
Experimental Design: Endometrial cancer specimens from 106 patients were evaluated. The methylation status of CDH13, Rassf1, SFRP1, SFRP2, SFRP4, SFRP5, p16, hMLH1, MGMT, APC, ATM, and WIF1 and mutations in the p53 and CDC4 genes were investigated. LSC was carried out to determine DNA ploidy. Fluorescence in situ hybridization was done with chromosome-specific centromeric probes to assess chromosomal instability.
Results: Univariate and multivariate analyses revealed that p53 mutation and lack of CDH13 hypermethylation associated positively with aneuploidy. Univariate analysis showed that aneuploidy, chromosomal instability, and lack of CDH13 hypermethylation as well as surgical stage were significantly predictive of death from endometrial cancer. Furthermore, multivariate analysis revealed that stage in combination with either DNA aneuploidy or lack of CDH13 hypermethylation was an independent prognostic factor.
Conclusion: These results suggest that analysis of DNA ploidy and methylation status of CDH13 may help predict clinical outcome in patients with endometrial cancer. Prospective randomized trials are needed to confirm the validity of an individualized approach, including determination of tumor ploidy and methylation status of CDH13, to management of endometrial cancer patients.
Activity of the Bcl-2 Family Inhibitor ABT-263 in a Panel of Small Cell Lung Cancer Xenograft Models
Authors: Shoemaker Alex R. , Mitten Michael J. , Adickes Jessica , Ackler Scott , Refici Marion , Ferguson Debra , Oleksijew Anatol , O'Connor Jacqueline M. , Wang Baole , Frost David J. , Bauch Joy , Marsh Kennan , Tahir Steven K. , Yang Xiufen , Tse Christin , Fesik Stephen W. , Rosenberg Saul H. , Elmore Steven W. 
Published: June 2008

Abstract
Purpose: The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models.
Experimental Design: A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison to standard cytotoxic agents, and induction of apoptosis.
Results: ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic schedules and was associated with significant induction of apoptosis.
Conclusions: ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent.
Preoperative Plasma Endoglin Levels Predict Biochemical Progression After Radical Prostatectomy
Authors: Svatek Robert S. , Karam Jose A. , Roehrborn Claus G. , Karakiewicz Pierre I. , Slawin Kevin M. , Shariat Shahrokh F. 
Published: June 2008

AbstractPurpose: Endoglin (CD105) is a transmembrane glycoprotein expressed by human vascular endothelial cells thought to play a pivotal role in endothelial cell proliferation. The aim of this study was to evaluate the association of preoperative plasma endoglin levels with established clinical and pathologic features of prostate cancer and disease progression after radical prostatectomy.Experimental Design: Preoperative plasma endoglin levels were measured in 425 patients who underwent radical prostatectomy for clinically localized prostate cancer using a commercially available ELISA assay. Multivariate logistic regression was used to test the association of plasma endoglin levels with biochemical progression after radical prostatectomy.Results: Median follow-up for patients alive at the time of analysis was 36.8 months (interquartile range, 44.1). Of 425 patients, 77 patients (18.1%) experienced biochemical progression after radical prostatectomy. Preoperative plasma endoglin levels were significantly elevated in patients with higher preoperative total serum prostate-specific antigen (P &lt; 0.001) and adverse pathologic features. Preoperative plasma endoglin was an independent predictor of biochemical progression after surgery after adjusting for the effects of standard preoperative and postoperative features (P &lt; 0.001 and P = 0.026, respectively).Conclusions: Preoperative plasma endoglin levels are associated with established features of advanced prostate cancer. More importantly, higher preoperative plasma endoglin levels are independent predictors of an increased risk of biochemical progression in patients treated with radical prostatectomy and bilateral pelvic lymphadenectomy.