bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Value of Body Mass Index in Locally Advanced Breast Cancer
Authors: Dawood Shaheenah , Broglio Kristine , Gonzalez-Angulo Ana M. , Kau Shu-Wan , Islam Rabiul , Hortobagyi Gabriel N. , Cristofanilli Massimo 
Published: March 2008

Abstract
Purpose: The purpose of this retrospective study was to determine the association and prognostic value of body mass index (BMI) at the time of initial diagnosis in patients with locally advanced breast cancer (LABC). The analysis includes the subsets of inflammatory (IBC) and noninflammatory (non-IBC LABC) breast cancer.
Experimental Design: We identified 602 patients who had LABC treated on prospective clinical trials. BMI was divided into three groups: (a) ≤24.9 (normal/underweight), (b) 25.0 to 29.9 (overweight), and (c) ≥30 (obese). Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards were used to determine associations between survival and BMI and to test for an interaction between BMI and breast cancer type.
Results: Eighty-two percent had non-IBC LABC and 18% had IBC. Obese patients tended to have a higher incidence of IBC compared with overweight and normal/underweight groups (P = 0.01). Median follow up was 6 years for all patients. Median overall survival (OS) and recurrence-free survival (RFS) were 8.8 and 5.9 years, respectively. Patients with LABC who were obese or overweight had a significantly worse OS and RFS (P = 0.001) and a higher incidence of visceral recurrence compared with normal/underweight patients. In a multivariable model, BMI remained significantly associated with both OS and RFS for the entire cohort. The interactions between BMI and LABC subsets and between BMI and menopausal status were not statistically significant.
Conclusion: Patients with LABC and high BMI have a worse prognosis. Evaluation of the biological factors associated with this observation can provide tools for additional therapeutic interventions.
Overall and Relapse-Free Survival in Oropharyngeal and Hypopharyngeal Squamous Cell Carcinoma Are Associated with Genotypes of T393C Polymorphism of the GNAS1 Gene
Authors: Lehnerdt Goetz F. , Franz Peter , Zaqoul Anwar , Schmitz Klaus J. , Grehl Sara , Lang Stephan , Schmid Kurt W. , Siffert Winfried , Jahnke Klaus , Frey Ulrich H. 
Published: March 2008

Abstract
Purpose: In previous studies, we have shown that the T allele of a specific single-nucleotide polymorphism (SNP) in the Gαs gene (T393C) correlates with increased Gαs expression and hence apoptosis. The T allele was associated with a favorable outcome in a variety of human cancers, e.g., carcinoma of the urinary bladder, kidney, and colorectum.
Experimental Design: The prognostic value of the T393C SNP was evaluated in an unselected series of patients treated with curative intent for oropharyngeal and hypopharyngeal squamous cell carcinomas, including all tumor stages with different therapeutic regimens. Genotype analysis was done using DNA from paraffin-embedded tissue samples from 202 patients (162 men, 40 women) with a median follow-up of 38 months (1-133 months). The various genotypes were correlated with relapse-free and overall survival.
Results: GNAS1 393C homozygous patients displayed a higher risk for disease progression than T393 homozygous patients (hazard ratio CC versus TT, 1.9; 95% confidence interval, 1.1-3.2; P = 0.019). The same genotype effect was observed for overall survival with CC genotypes at higher risk for death compared with TT genotypes (hazard ratio, 1.7; 95% confidence interval, 1.1-2.9; P = 0.015). Multivariate analysis showed that, besides American Joint Committee on Cancer stage, tumor localization, and gender, the T393C polymorphism was an independent prognostic factor for disease progression and death.
Conclusion: The T393C SNP could be considered as a genetic marker to predict the clinical course of patients suffering from oropharyngeal and hypopharyngeal cancer.
Resveratrol Exerts Antiproliferative Activity and Induces Apoptosis in Waldenström's Macroglobulinemia
Authors: Roccaro Aldo M. , Leleu Xavier , Sacco Antonio , Moreau Anne-Sophie , Hatjiharissi Evdoxia , Jia Xiaoying , Xu Lian , Ciccarelli Bryan , Patterson Christopher J. , Ngo Hai T. , Russo Domenico , Vacca Angelo , Dammacco Franco , Anderson Kenneth C. , Ghobrial Irene M. , Treon Steven P. 
Published: March 2008

AbstractPurpose: Resveratrol (3,4',5-tri-hydroxy-trans-stilbene) is an antioxidant constituent of a wide variety of plant species including grapes. It has gained considerable attention because of its anticancer properties, as shown in solid and hematologic malignancies. Whether resveratrol could inhibit proliferation or induce cytotoxicity in Waldenström's macroglobulinemia (WM) was investigated.Experimental Design: We studied resveratrol-induced inhibition of proliferation and induction of cytotoxicity in WM cell lines, WM primary tumor cells, IgM-secreting cells, and peripheral blood mononuclear cells. The mechanisms of action and different signaling pathways involved were studied using Western blot and gene expression profile analysis. Resveratrol activity was also evaluated in the bone marrow microenvironment. We finally investigated whether or not resveratrol could have any synergistic effect if used in combination with other drugs widely used in the treatment of WM.Results: Resveratrol inhibited proliferation and induced cytotoxicity against WM cells, IgM-secreting cells, as well as primary WM cells, without affecting peripheral blood mononuclear cells; down-regulated Akt, extracellular signal-regulated kinase mitogen-activated protein kinases, and Wnt signaling pathways, as well as Akt activity; induced cell cycle arrest and apoptosis; and triggered c-Jun-NH2-terminal-kinase activation, followed by the activation of intrinsic and extrinsic caspase pathways. Lastly, adherence to bone marrow stromal cells did not confer protection to WM cells against resveratrol-induced cytotoxicity. Furthermore, resveratrol showed synergistic cytotoxicity when combined with dexamethasone, fludarabine, and bortezomib.Conclusion: Our data show that resveratrol has significant antitumor activity in WM, providing the framework for clinical trials in this disease.
Cytotoxicity and Proteomics Analyses of OSU03013 in Lung Cancer
Authors: Tan Yi-Hung , Lee Kung-Hsueh , Lin Topp , Sun Ying-Chieh , Hsieh-Li Hsiu Mei , Juan Hsueh-Fen , Wang Yi-Ching 
Published: March 2008

Abstract
Purpose: Most lung cancer patients have some resistance to and suffer from side effects of conventional chemotherapy. Thus, identification of a novel anticancer drug with better target selectivity for lung cancer treatment is urgently needed.
Experimental Design: In order to investigate whether OSU03013, a derivative of celecoxib, can be a potential drug for lung cancer treatment, we examined its cytotoxicity mechanisms by flow cytometry and phosphatidylserine staining in A549, CL1-1, and H1435 lung cancer cell lines, which are resistant to the conventional drug, cisplatin. In addition, we identified the affected proteins by proteomics and confirmed the selected proteins by Western blot analysis. We examined the interaction between OSU03013 and potential target protein by molecular modeling.
Results: Our results indicated that OSU03013 had low-dose (1∼4 μM) cytotoxicity in all lung cancer cell lines tested 48 hours posttreatment. OSU03013 caused cell cycle G1 phase arrest and showed phosphatidylserine early apoptosis via endoplasmic reticulum stress. Several proteins such as heat shock protein 27, 70, and 90, CDC2, α-tubulin, annexin A3, cAMP-dependent protein kinase, glycogen synthase kinase 3-beta, and β-catenin were identified by proteomics and confirmed by Western blot. In addition, molecular modeling showed that OSU03013 competes with ATP to bind to cAMP-dependent protein kinase.
Conclusions: We identified for the first time that OSU03013 inhibits cAMP-dependent protein kinase activity and causes dephosphorylation of glycogen synthase kinase 3-beta leading to β-catenin degradation, which is often overexpressed in lung cancer. Our molecular and proteomic results show the potential of OSU03013 as an anticancer drug for lung cancer.
IMP3 Predicts Aggressive Superficial Urothelial Carcinoma of the Bladder
Authors: Sitnikova Lioudmila , Mendese Gary , Liu Qin , Woda Bruce A. , Lu Di , Dresser Karen , Mohanty Sambit , Rock Kenneth L. , Jiang Zhong 
Published: March 2008

Abstract
Purpose: In this study, we investigated whether an oncofetal protein, IMP3, can serve as a new biomarker to predict progression and metastasis of early-stage urothelial carcinoma of the bladder.
Experimental Design: The expression of IMP3 in 242 patients with primary superficial bladder urothelial carcinoma and metastatic urothelial carcinoma was evaluated by immunohistochemistry. Patients with primary superficial urothelial carcinoma of the bladder were further investigated by use of survival analysis.
Results: Twenty percent (42 of 214) of primary superficial urothelial carcinomas and 93% (26 of 28) of metastatic urothelial carcinomas expressed IMP3. Kaplan-Meier plots and log-rank tests showed that patients with IMP3-positive tumors had a much lower progression-free survival (P = 0.0002) and disease-free survival rate (P = 0.0067) than did those with IMP3-negative tumors. The 5-year progression-free and disease-free survival rates were 91% and 94% in IMP3-negative patients versus 64% and 76% in IMP3-positive patients, respectively. Sixty percent of IMP3-positive patients with superficial invasive urothelial carcinoma at initial diagnosis went on to develop metastases, whereas no metastasis was found in IMP3-negative patients (P = 0.0017). In the multivariable Cox analysis, patients with IMP3 expression in their superficial urothelial carcinomas subsequently developed invasive tumors or metastasis at a rate that was about five times greater than cases without expression of IMP3 adjusting for other well-known clinical variables (tumor stage and grade, etc.).
Conclusions: Our findings indicate that IMP3 is an independent prognostic marker that can identify a group of patients with a high potential to develop progression and who might benefit from early aggressive therapy.
Toll-like Receptor 4 Mediates an Antitumor Host Response Induced by Salmonella choleraesuis
Authors: Lee Che-Hsin , Wu Chao-Liang , Shiau Ai-Li 
Published: March 2008

Abstract
Purpose: We have shown tumor-targeting and antitumor activities of an attenuated Salmonella choleraesuis in various tumor models. Meanwhile, host factors, including innate and adaptive immune responses, play roles in Salmonella-induced antitumor activity. Toll-like receptor 4 (TLR4) is identified as a signaling receptor for lipopolysaccharide derived from Gram-negative bacteria. However, the detailed mechanism of the S. choleraesuis–induced antitumor immune response via TLR4 remained uncertain.
Experimental Design: Herein, we used wild-type C3H/HeN mice and TLR4-deficient C3H/HeJ mice to study the role of TLR4 in the antitumor immune responses induced by S. choleraesuis.
Results: The amounts of S. choleraesuis were cleared more rapidly from the normal organs in C3H/HeN mice than those in C3H/HeJ mice. Tumors in C3H/HeN mice treated with S. choleraesuis were significantly smaller than those treated with PBS. By contrast, in TLR4-deficient mice, there was a slight difference in inhibition of tumor growth. Meanwhile, we found that S. choleraesuis significantly up-regulated IFN-γ, IFN-inducible chemokines CXCL9 (MIG), and CXCL10 (IP-10) productions in C3H/HeN mice, but not in C3H/HeJ mice. Furthermore, immunohistochemical staining of the tumors revealed less intratumoral microvessel density, more infiltration of macrophages, neutrophils, CD4+ and CD8+ T cells, and cell death in C3H/HeN mice after S. choleraesuis treatment compared with those in C3H/HeJ mice. The interaction between TLR4 and S. choleraesuis seemed to polarize the T-cell response to a T helper 1–dominant state.
Conclusions: These results suggest TLR4 may play an important role in the molecular mechanism of S. choleraesuis–induced host antitumor responses.
Current Status and Future Prospects for Satraplatin, an Oral Platinum Analogue
Authors: Choy Hak , Park Clinton , Yao Min 
Published: March 2008

Abstract
Platinum drugs are major chemotherapeutic agents that are used alone or in combination with other systemic agents and/or radiation therapy in the management of many human malignancies. All three platinum drugs approved by the Food and Drug Administration, cisplatin, carboplatin, and oxaliplatin, are administrated intravenously. Satraplatin is the first orally administered platinum drug under active clinical investigation. Satraplatin and its major metabolite, JM118, have shown antineoplastic activity in in vitro, in vivo, and in clinical settings. Use of satraplatin as an alternative platinum cytotoxic agent is particularly attractive because of the convenience of administration, milder toxicity profile, lack of cross-resistance with cisplatin, theoretical advantage as a radiosensitizer, and activity in cancers historically nonresponsive to platinum drugs. The most mature clinical data for satraplatin come from the recently completed phase III trial that investigated the efficacy of satraplatin and prednisone on hormone-refractory prostate cancer patients who had failed a course of other chemotherapy agents. Preliminary reports show that the combination is statistically superior to placebo and prednisone in multiple end points, including progression-free survival, prostate-specific antigen response, objective tumor response, pain response, and duration of pain response. The difference in overall survival, however, did not reach statistical significance.
Vinflunine: A New Microtubule Inhibitor Agent
Authors: Bennouna Jaafar , Delord Jean-Pierre , Campone Mario , Nguyen Laurent 
Published: March 2008

AbstractVinflunine (Javlor) is the first fluorinated microtubule inhibitor belonging to the Vinca alkaloids family. Vinflunine is obtained by semisynthesis using superacidic chemistry to selectively introduce two fluorine atoms at the 20′ position of the catharanthine moiety. This compound has been selected for clinical development on the basis of encouraging preclinical activity that warrants study in patients with a wide spectrum of solid tumors. Clinically significant activity has been seen in phase II studies, mainly in the treatment of transitional cell carcinoma of the urothelial tract, non–small cell lung cancer, and carcinoma of the breast. Vinflunine is currently in phase III trial assessment in patients with (second line) transitional cell carcinoma of the urothelium and first-line advanced breast cancer. The efficacy of vinflunine in patients with advanced non–small cell lung cancer previously treated with a platinum-containing regimen was confirmed by a large phase III trial.
Improving the Quality of Abstract Reporting for Phase I Cancer Trials
Authors: Strevel Elizabeth L. , Chau Nicole G. , Pond Gregory R. , Murgo Anthony J. , Ivy Percy S. , Siu Lillian L. 
Published: March 2008

Abstract
Purpose: Conference abstracts of phase I trials (P1T) communicate important anticancer drug development information. Our objectives were to determine elements essential for good P1T abstract reporting, to assess the quality of P1T abstracts submitted to American Society of Clinical Oncology (ASCO) meetings, and to propose reporting guidelines.
Experimental Design: A survey of developmental therapeutics experts established elements of P1T reporting quality, and a scoring system was generated. All P1T abstracts published in ASCO Annual Proceedings from 1997 to 2006 were reviewed, and the scoring system was applied.
Results: A survey was distributed twice to 69 experts, with a response rate of 39% (27 of 69). Experts rated 37 elements using a five-point scale, and elements with mean ratings over 3.75 were included in the final scoring system. One thousand six hundred and eighty three P1T abstracts were reviewed. A positive and linear association was observed between average expert rating of the elements and the proportion of P1T abstracts including those elements (Spearman correlation coefficient, ρ = 0.60, P &lt; 0.001). The median for all 1,683 abstracts was 62.5% (range, 25-95%; SD, 12.3%). Year of presentation was found to be significantly associated with higher quality scores (ρ = 0.20, P &lt; 0.001), with later years possessing better quality scores. The quality score was statistically significant as a predictor of type of presentation (odds ratio, 1.10; 95% confidence interval, 1.02-1.19 per 10% increase; P = 0.014), with oral presentations having the highest scores.
Conclusions: The quality of P1T abstract reporting at ASCO has improved over time, although there is room for optimization. The quality of P1T abstract reporting may be enhanced using guidelines derived from our expert consensus.
Overexpression of PTEN in ovarian cancer cells suppresses i.p. dissemination and extends survival in mice
Authors: Takei Yuji , Saga Yasushi , Mizukami Hiroaki , Takayama Takeshi , Ohwada Michitaka , Ozawa Keiya , Suzuki Mitsuaki 
Published: March 2008

Abstract
The main mode of progression of ovarian cancer is peritoneal dissemination, and its inhibition may lead to improved outcome. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) reportedly inhibits the proliferation, migration, and invasion of cancer cells. The purpose of this study is to explore the possibility of PTEN gene therapy for ovarian cancer. We transfected the ovarian cancer cell line SHIN-3 [vascular endothelial growth factor (VEGF)–hypersecretory cell line] with PTEN or luciferase (LUC)–expressing plasmid. After selection, PTEN-overexpressing cells (SHIN-3/PTEN) and control cells (SHIN-3/LUC) were obtained. SHIN-3/PTEN implanted s.c. into nude mice was examined for the change in tumor diameter and the number of new blood vessels. Mice with peritoneally disseminated tumors created by i.p. inoculation of the same cells were examined for changes in body weight and abdominal circumference and for survival time. The growth of s.c. SHIN-3/PTEN was significantly lower than that of control (P &lt; 0.001). Compared with controls, mice with i.p. inoculated SHIN-3/PTEN showed significantly smaller increases in the body weight and abdominal circumference (P &lt; 0.01) and a significantly longer survival time (P &lt; 0.05). VEGF concentration in the supernatant of SHIN-3/PTEN was about half that of controls (P &lt; 0.05). The number of new blood vessels in SHIN-3/PTEN was significantly smaller than that in controls (P &lt; 0.001). Overexpression of PTEN suppressed tumor growth and peritoneal dissemination of VEGF-hypersecretory ovarian cancer cells and prolonged the survival time of the mice with peritoneal disseminated tumor. PTEN gene therapy could have therapeutic potential for ovarian cancer and exerts some of this effect by inhibiting angiogenesis. [Mol Cancer Ther 2008;7(3):704–11]
Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds
Authors: Benedetti Valentina , Perego Paola , Luca Beretta Giovanni , Corna Elisabetta , Tinelli Stella , Righetti Sabina Carla , Leone Roberto , Apostoli Piero , Lanzi Cinzia , Zunino Franco 
Published: March 2008

AbstractBecause cytotoxic stress elicits various signaling pathways that may be implicated in cell survival or cell death, their alterations may have relevance in the development of platinum-resistant phenotype. Thus, in the present study, we investigated cell response to the epidermal growth factor receptor (EGFR) inhibitor gefitinib of ovarian carcinoma cell lines, including cells selected for resistance to cisplatin (IGROV-1/Pt1) and oxaliplatin (IGROV-1/OHP). Resistant sublines exhibited a marked decrease in sensitivity to gefitinib and resistance to apoptosis. Gefitinib was capable of inhibiting the phosphorylation of EGFR in all the studied cell lines. The Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) kinases, which act downstream of EGFR, were constitutively active in the three cell lines, but phospho-ERK1/2 levels were increased in the two resistant sublines. This feature was associated with reduced sensitivity to the MEK1/2 inhibitor U0126. Pretreatment of resistant cells with U0126 resulted in restoration of sensitivity to gefitinib. Gefitinib was more effective in inhibiting ERK1/2 and Akt phosphorylation in IGROV-1 cells than in IGROV-1/OHP and IGROV-1/Pt1 cells. Phospho-p38 was up-regulated in the resistant sublines, indicating the concomitant activation of distinct mitogen-activated protein kinases. The up-regulation of phospho-p38 was associated with a peculiar localization of EGFR, which, in resistant sublines, was mainly internalized. In conclusion, our results indicate that the development of resistance to platinum drugs is associated with multiple alterations including deregulation of survival pathways activated by EGFR resulting in a reduced cellular response to gefitinib. [Mol Cancer Ther 2008;7(3):679–87]
Dicoumarol down-regulates human PTTG1/Securin mRNA expression through inhibition of Hsp90
Authors: Hernández Agustín , López-Lluch Guillermo , Bernal Juan A. , Navas Plácido , Pintor-Toro José A. 
Published: March 2008

Abstract
Securin, the natural inhibitor of sister chromatid untimely separation, is a protooncogene overexpressed in tumors. Its protein levels correlate with malignancy and metastatic proneness. Dicoumarol, a long-established oral anticoagulant, is a new Hsp90 inhibitor that represses PTTG1/Securin gene expression and provokes apoptosis through a complex trait involving both intrinsic and extrinsic pathways. Dicoumarol activity as an Hsp90 inhibitor is confirmed by smaller levels of Hsp90 clients in treated cells and inhibition of in vivo heat shock luciferase activity recovery assays. Likewise, established Hsp90 inhibitors (17-allylamino-geldanamycin and novobiocin) repress PTTG1/Securin gene expression. Also, overexpression of human Hsp90 in yeast makes them hypersensitive to dicoumarol. Both apoptosis and PTTG1/Securin gene repression exerted by dicoumarol in cancer cells are independent of three of the most important signaling pathways affected by Hsp90 inhibition: nuclear factor-κB, p53, or Akt/protein kinase B signaling pathways. However, effects on PTTG1/Securin could be partially ascribed to inhibition of the Ras/Raf/extracellular signal-regulated kinase pathway. Overall, we show that expression of PTTG1/Securin gene is Hsp90 dependent and that dicoumarol is a bona fide Hsp90 inhibitor. These findings are important to understand the mode of action of Hsp90 inhibitors, mechanisms of action of dicoumarol, and Securin overexpression in tumors. [Mol Cancer Ther 2008;7(3):474–82]