bluuebunny/crossref_metadata_2025_split huggingface dataset:
PTEN Loss Does Not Predict for Response to RAD001 (Everolimus) in a Glioblastoma Orthotopic Xenograft Test Panel
Authors: Yang Lin , Clarke Michelle J. , Carlson Brett L. , Mladek Ann C. , Schroeder Mark A. , Decker Paul , Wu Wenting , Kitange Gaspar J. , Grogan Patrick T. , Goble Jennie M. , Uhm Joon , Galanis Evanthia , Giannini Caterina , Lane Heidi A. , James C. David , Sarkaria Jann N. 
Published: June 2008

Abstract
Purpose: Hyperactivation of the phosphatidylinositol 3-kinase/Akt signaling through disruption of PTEN function is common in glioblastoma multiforme, and these genetic changes are predicted to enhance sensitivity to mammalian target of rapamycin (mTOR) inhibitors such as RAD001 (everolimus).
Experimental Design: To test whether PTEN loss could be used as a predictive marker for mTOR inhibitor sensitivity, the response of 17 serially transplantable glioblastoma multiforme xenografts was evaluated in an orthotopic therapy evaluation model. Of these 17 xenograft lines, 7 have either genomic deletion or mutation of PTEN.
Results: Consistent with activation of Akt signaling, there was a good correlation between loss of PTEN function and elevated levels of Akt phosphorylation. However, of the 7 lines with disrupted PTEN function, only 1 tumor line (GBM10) was significantly sensitive to RAD001 therapy (25% prolongation in median survival), whereas 1 of 10 xenograft lines with wild-type PTEN was significantly sensitive to RAD001 (GS22; 34% prolongation in survival). Relative to placebo, 5 days of RAD001 treatment was associated with a marked 66% reduction in the MIB1 proliferation index in the sensitive GBM10 line (deleted PTEN) compared with a 25% and 7% reduction in MIB1 labeling index in the insensitive GBM14 (mutant PTEN) and GBM15 (wild-type PTEN) lines, respectively. Consistent with a cytostatic antitumor effect, bioluminescent imaging of luciferase-transduced intracranial GBM10 xenografts showed slowed tumor growth without significant tumor regression during RAD001 therapy.
Conclusion: These data suggest that loss of PTEN function is insufficient to adequately predict responsiveness to mTOR inhibitors in glioblastoma multiforme.
MDM2 Promoter Polymorphism and Pancreatic Cancer Risk and Prognosis
Authors: Asomaning Kofi , Reid Amy E. , Zhou Wei , Heist Rebecca S. , Zhai Rihong , Su Li , Kwak Eunice L. , Blaszkowsky Lawrence , Zhu Andrew X. , Ryan David P. , Christiani David C. , Liu Geoffrey 
Published: June 2008

Abstract
Purpose: The mouse double minute 2 homologue (MDM2) -309T/G promoter polymorphism has been associated recently with the development and prognosis of a variety of tumors. The G allele is associated with increased affinity for Sp1 binding and higher MDM2 mRNA and protein levels, leading to diminished tumor suppressor activity of the p53 pathway. We hypothesized that the G allele is also associated with increased risk and worse outcome in pancreatic cancer.
Experimental Design: We evaluated the association between MDM2 309T/G and the risk of histologically confirmed pancreatic adenocarcinoma at Massachusetts General Hospital using unconditional logistic regression (123 cases and 372 controls). Complete overall survival and progression-free survival data were also available for 109 newly diagnosed patients.
Results: The adjusted odds ratios (95% confidence intervals) of pancreatic cancer associated with the MDM2 T/G and G/G genotypes compared with TT were 1.89 (1.20-2.99) and 2.07 (1.03-4.16), respectively (adjusting for age, gender, smoking status, and pack-years of smoking). In Cox proportional hazards model with the wild-type T/T genotype as the reference category and adjusting for stage, treatment, and performance status, both the heterozygous T/G and the homozygous G/G genotypes were associated with decreased progression-free survival [adjusted hazard ratio (95% confidence interval), 1.67 (0.98-2.84) for T/G and 2.28 (1.11-4.71) for G/G] and overall survival [2.64 (1.23-5.67) for T/G and 3.12 (1.22-7.91) for G/G].
Conclusions: The G allele of the MDM2 -309T/G polymorphism is associated with 2- to 3-fold increase risk and progression of pancreatic adenocarcinoma and a corresponding decrease in survival.
Cytokeratin 10 and Cytokeratin 19: Predictive Markers for Poor Prognosis in Hepatocellular Carcinoma Patients after Curative Resection
Authors: Yang Xin-Rong , Xu Yang , Shi Guo-Ming , Fan Jia , Zhou Jian , Ji Yuan , Sun Hui-Chuan , Qiu Shuang-Jian , Yu Bing , Gao Qiang , He Yi-Zhou , Qin Weng-Zhen , Chen Rong-Xin , Yang Guo-Huan , Wu Bing , Lu Qing , Wu Zhi-Quan , Tang Zhao-You 
Published: June 2008

Abstract
Purpose: Cytokeratin 10 (CK10) was found to be expressed differently in human hepatocellular carcinoma (HCC) cell lines with different metastatic potentials in our previous research. The aim of this study was to assess the value of CK10 alone or in combination with cytokeratin 19 (CK19) in predicting tumor recurrence after curative resection in HCC patients.
Experimental Design: CK10 expression in stepwise metastatic HCC cell lines and tumor tissues from 50 HCC patients was investigated using immunofluorescence assay, quantitative real-time reverse transcription-PCR, and Western blot analyses. Tumor tissue microarrays of 300 HCC patients who underwent curative resection between 1997 and 2000 were used to detect the expressions of CK10 and CK19. Clinicopathologic data for these patients were evaluated. The prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests.
Results: CK10 was overexpressed in the high metastatic HCC cell line and in tumor tissues of recurrent patients. Both univariate and multivariate analyses revealed that CK10 was a significant predictor for overall survival (OS) and disease-free survival, and that CK19 was a significant predictor for OS. CK10 expression was correlated with poor prognosis regardless of α-fetoprotein, tumor-node-metastasis stage, and vascular invasion. The 7-year OS and disease-free survival rates in CK10+ and/or CK19+ patients were 30.0% and 37.6%, respectively, which were significantly lower than that of CK10−/CK19− patients (56.1% and 60.0%, respectively; P &lt; 0.001).
Conclusion: CK10 is associated with HCC invasiveness. CK10 alone, or in combination with CK19, can be a novel predictor for poor prognosis of HCC patients after curative resection.
Leveraging Exploratory Investigational New Drug Studies to Accelerate Drug Development
Authors: Jacobson-Kram David , Mills George 
Published: June 2008

Abstract
In 2006, the U.S. Food and Drug Administration published its guide on exploratory investigational new drug (IND) studies with the goal of making the approach to early-stage, pilot clinical trials more flexible within the context of current regulations. The exploratory IND allows sponsors to initiate clinical trials of limited scale with reduced preclinical requirements. These studies may be important vehicles for the conduct of proof-of-principle pharmacodynamic investigations of highly potent molecules, for bioavailability studies that require only a single drug dose to be administered, and for imaging trials that permit critical dosimetry and biodistribution investigations of new molecules. These trials were done with no therapeutic intent and must be followed by traditional dose-escalation investigations that are supported by standard preclinical toxicologic and pharmacologic studies. To the extent that they allow early evaluations of essential drug characteristics that can only be obtained in humans, exploratory IND trials have the potential to limit the cost and improve the development times of new agents.
The Development of Phase I Cancer Trial Methodologies: the Use of Pharmacokinetic and Pharmacodynamic End Points Sets the Scene for Phase 0 Cancer Clinical Trials
Authors: Calvert A. Hilary , Plummer Ruth 
Published: June 2008

Abstract
Although the concept of a phase 0 trial is a relatively new one, there has been a slowly increasing trend toward basing early clinical trial designs on pharmacokinetic and pharmacodynamic end points that has been developing over many years. This article will review the early cancer trial methodologies and the various techniques that have been used to refine them. Several illustrative examples will be presented showing their relevance to trial designs using pharmacodynamic end points and targeted agents. Some criteria for characterizing suitable phase 0 end points are suggested. Four trial designs that are essentially developed for cytotoxic agents using the maximal tolerated dose as an end point are described. Although these trials were not designed with the use of more sophisticated pharmacodynamic end points (such as the measurement of the effect of a targeted agent on its target), they have been developed to optimize the speed with which a dose needed to achieve a particular effect can be determined and are, to this extent, relevant to the design of studies with pharmacodynamic end points.
Oncologic Phase 0 Trials Incorporating Clinical Pharmacodynamics: from Concept to Patient
Authors: Doroshow James H. , Parchment Ralph E. 
Published: June 2008

Abstract
The U.S. Food and Drug Administration recently issued an Exploratory Investigational New Drug (IND) guidance that provides a platform for the evaluation of targeted anticancer agents in small, early-phase human clinical trials that can be used to establish the feasibility of proof-of-principle target modulation assays, as well as the preliminary pharmacokinetics and molecular imaging potential of new anticancer molecules. The exploratory IND allows for reduced requirements for manufacturing and toxicologic assessment. Early clinical trials done in this fashion have no therapeutic intent. In this series of articles in CCR Focus, the development of this new IND mechanism, its effect on clinical trial design and clinical pharmacodynamics, the ethical implications of nontherapeutic clinical investigations, and the perspective of the pharmaceutical industry on this approach are examined.
Phase 0 Trials: An Industry Perspective
Authors: Eliopoulos Helen , Giranda Vincent , Carr Robert , Tiehen Rita , Leahy Terri , Gordon Gary 
Published: June 2008

Abstract
Worldwide, cancer is a leading cause of morbidity and mortality. An increased understanding of the disease and its process has resulted in a multitude of new targeted therapies. The costs as well as time from drug discovery to market, however, remain staggeringly high and protracted, with the majority of compounds never reaching phase III. The concept of an exploratory or phase 0 trial was introduced as a mechanism to enhance and accelerate the overall process of new oncologic drug development. Performance of a phase 0 study allows researchers to better understand the pharmacokinetic and pharmacodynamic properties of compounds in human subjects before initiation of phase I trials. Data gleaned from a phase 0 trial are beneficial not only in prioritizing promising compounds but also in allowing the modification of phase I study design before initiation. To date, few researchers have taken advantage of the potential benefits of phase 0 trials. This review focuses on the purpose as well as the potential merits of phase 0 trials from the perspective of a pharmaceutical company. The review summarizes the experience of a team of researchers with ABT-888, a novel poly (ADP-ribose) polymerase agent that inhibits an enzyme critical for repairing damage to DNA, which is one of the first compounds to be investigated using the phase 0 clinical trial design.
Are There Any Ethnic Differences in Molecular Predictors of Erlotinib Efficacy in Advanced Non-Small Cell Lung Cancer?
Authors: Ahn Myung-Ju , Park Byeong-Bae , Ahn Jin Seok , Kim Sang We , Kim Heung-Tae , Lee Jong Seog , Kang Jin Hyung , Cho Jae Yong , Song Hong Suk , Park Se Hoon , Sohn Chang Hak , Shin Sang Won , Choi Jin Hyuck , Ki Chang-Seok , Park Chan Keum , Holmes Alison J. , Jänne Pasi A. , Park Keunchil 
Published: June 2008

Abstract
Purpose: This study investigated possible molecular predictors of outcome in Korean patients with advanced non-small cell lung cancer treated with erlotinib.
Experimental Design: One hundred and twenty patients received erlotinib and were followed prospectively. Ninety-two tissue samples were analyzed for epidermal growth factor receptor (EGFR) gene mutations (exons 18, 19, and 21), 88 for EGFR gene amplification by real-time PCR, and 75 for EGFR protein expression by immunohistochemistry.
Results: The overall tumor response rate was 24.2% (complete response, 4; partial response, 25) with 56.7% of disease control rate. With a median follow-up of 23.6 months, the median time to progression (TTP) was 2.7 months and the median overall survival was 12.9 months. EGFR gene mutations were found in 26.1% (24 of 92), EGFR gene amplification in 40.9% (36 of 88), and EGFR protein expression in 72% (54 of 75). There was a strong association between EGFR gene mutations and gene amplification (γ = 0.241). Patients with EGFR gene mutations or gene amplification showed both better response rate (58.3% versus 16.2%, P &lt; 0.001; 41.7% versus 17.3%, P = 0.012) and TTP (8.6 versus 2.5 months, P = 0.003; 5.8 versus 1.8 months, P &lt; 0.001) and overall survival (not reached versus 10.8 months, P = 0.023; not reached versus 10.1 months, P = 0.033). By multivariate analysis, EGFR gene mutation was the only significant molecular predictor for TTP (hazard ratio, 0.47; 95% confidence interval, 0.25-0.89).
Conclusions: Our findings indicate that EGFR gene mutation is a more predictive marker for improved TTP than EGFR gene amplification in erlotinib-treated Korean non-small cell lung cancer patients. Prospective studies from diverse ethnic backgrounds are required to determine the exact role of these molecular markers.
Intratumoral Coadministration of Hyaluronidase Enzyme and Oncolytic Adenoviruses Enhances Virus Potency in Metastatic Tumor Models
Authors: Ganesh Shanthi , Gonzalez-Edick Melissa , Gibbons Douglas , Van Roey Melinda , Jooss Karin 
Published: June 2008

Abstract
Purpose: Evaluate the codelivery of hyaluronidase enzyme with oncolytic adenoviruses to determine whether it improves the spread of the virus throughout tumors, thereby leading to a greater overall antitumor efficacy in tumor models.
Experimental Design: The optimal dose of hyaluronidase that provided best transduction efficiency and spread of a green fluorescent protein (GFP)-expressing adenovirus within tumors was combined with oncolytic viruses in tumor models to determine whether the combination treatment results in an improvement of antitumor efficacy.
Results: In mice injected with the adenovirus Ad5/35GFP and an optimal dose of hyaluronidase (50 U), a significant increase in the number of GFP-expressing cells was observed when compared with animals injected with virus only (P &lt; 0.0001). When the oncolytic adenoviruses Ad5OV or Ad5/35 OV (OV-5 or OV5T35H) were codelivered with 50 U of hyaluronidase, a significant delay in tumor progression was observed, which translated into a significant increase in the mean survival time of tumor-bearing mice compared with either of the monotherapy-treated groups (P &lt; 0.0001). Furthermore, the mice that received the combination of Ad5/35 OV and hyaluronidase showed the best antitumor efficacy. Importantly, the combination treatment did not increase the metastatic potential of the tumors. Lastly, the increase in virus potency observed in animals injected with both enzyme and virus correlated with enhanced virus spread throughout tumors.
Conclusion: Antitumor activity and overall survival of mice bearing highly aggressive tumors are significantly improved by codelivery of oncolytic adenoviruses and hyaluronidase when compared with either of the monotherapy-treated groups, and it may prove to be a potent and novel approach to treating patients with cancer.
Interaction of Cisplatin with the Human Organic Cation Transporter 2
Authors: Filipski Kelly K. , Loos Walter J. , Verweij Jaap , Sparreboom Alex 
Published: June 2008

AbstractPurpose: Cisplatin is predominantly eliminated in the urine through active secretion. As the solute carrier organic cation transporter 2 (OCT2) is highly expressed in the basolateral membrane of proximal tubules, we determined its contribution to cisplatin transport and assessed the relation of variation in the gene encoding OCT2 (SLC22A2) with the disposition of cisplatin.Experimental Design: Cell lines were transfected using the Flp-In 293 system with the full-length OCT2 cDNA, and platinum concentrations were measured using flameless atomic absorption spectrometry. Pharmacokinetic data were available from 106 cancer patients, and DNA was screened for eight nonsynonymous SLC22A2 variants using direct sequencing.Results: mRNA expression was 36-fold higher and uptake of the model substrate tetraethylammonium was significantly increased (P &lt; 0.0001) in OCT2-transfected cells compared with empty vector-transfected controls. OCT2-mediated transport of cisplatin was saturable, and uptake was increased by ∼4-fold (P &lt; 0.0001) relative to control cells. Cisplatin inhibited OCT2-mediated transport of tetraethylammonium by up to 97%. The mean ± SD systemic clearance of unbound cisplatin-derived platinum in the patient population was 29.2 ± 8.39 L/h, and renal clearance was particularly variable. Only one single nucleotide polymorphism (Ala270Se; rs316019) was identified (minor allele frequency, 7.6%), and it was not found to be associated with any of the studied pharmacokinetic variables (P &gt; 0.05).Conclusion: These findings support the hypothesis that OCT2 is a key renal transporter involved in cisplatin elimination. However, known variants in SLC22A2 do not substantially contribute to explaining interindividual pharmacokinetic variability, suggesting that other mechanisms, controlling OCT2 expression, might be involved.
Suppression of proHB-EGF Carboxy-Terminal Fragment Nuclear Translocation: A New Molecular Target Therapy for Gastric Cancer
Authors: Shimura Takaya , Kataoka Hiromi , Ogasawara Naotaka , Kubota Eiji , Sasaki Makoto , Tanida Satoshi , Joh Takashi 
Published: June 2008

Abstract
Purpose: Inactivation of epidermal growth factor (EGF) receptor (EGFR) represents a promising strategy for the development of selective therapies against epithelial cancers and has been extensively studied as a molecular target for cancer therapy. However, little attention has been paid to remnant cell-associated domains created by cleavage of EGFR ligands. The present study focused on recent findings that cleavage of membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF), an EGFR ligand, induces translocation of the carboxyl-terminal fragment (CTF) of HB-EGF from the plasma membrane to the nucleus and regulates cell cycle.
Experimental Design: Two gastric cancer cell lines, MKN28 and NUGC4, were used. KB-R7785, an inhibitor of proHB-EGF shedding, was used to suppress HB-EGF-CTF nuclear translocation with cetuximab, which inhibits EGFR phosphorylation. Cell growth was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, apoptosis was evaluated by assay of caspase-3 and caspase-7, and cell cycle was investigated by flow cytometry.
Results: Immunofluorescence study confirmed that KB-R7785 inhibited HB-EGF-CTF nuclear translocation under conditions of proHB-EGF shedding induction by 12-O-tetradecanoylphorbol-13-acetate in gastric cancer cells. KB-R7785 inhibited cell growth in a dose-dependent manner and high-dose KB-R7785 induced apoptosis. Moreover, KB-R7785 induced cell cycle arrest and increased sub-G1 DNA content. KB-R7785 suppressed cyclin A and c-Myc expression. All effects of KB-R7785 were reinforced by combination with cetuximab.
Conclusions: These results suggest that both inhibition of EGFR phosphorylation and inhibition of HB-EGF-CTF nuclear translocation play crucial roles in inhibitory regulation of cancer cell growth. Suppression of HB-EGF-CTF nuclear translocation might offer a new strategy for treating gastric cancer.
BRCA1 and BRCA2 Mutation Prevalence and Clinical Characteristics of a Population-Based Series of Ovarian Cancer Cases from Denmark
Authors: Soegaard Marie , Kjaer Susanne Kruger , Cox Mark , Wozniak Eva , Høgdall Estrid , Høgdall Claus , Blaakaer Jan , Jacobs Ian J. , Gayther Simon A. , Ramus Susan J. 
Published: June 2008

Abstract
Purpose: To evaluate the prevalence of BRCA1 and BRCA2 mutations and associations with clinical correlates of disease in a population-based series of ovarian cancer cases from Denmark.
Methods: DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to analyze the BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer. We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors.
Results: Deleterious BRCA1 or BRCA2 mutations were identified in 26 cases; thus, mutations in these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations in Denmark. We identified several differences between mutation carriers and noncarriers: mutation carriers were diagnosed at a significantly early age (median, 49 and 61 years, respectively; P = 0.0001); the frequency of BRCA1 mutation carriers was 23% for women diagnosed &lt;40 years, 15% for 40 to 49 years, 4% for 50 to 59 years, and 2% for ≥60 years (P = 0.00002); ovarian cancer in carriers was diagnosed at a later stage (P = 0.002) and tumors were of poorer grade (P = 0.0001); and first-degree relatives of mutation carriers had greater relative risks of both ovarian cancer [10.6 (95% confidence interval, 4.2-26.6); P &lt; 0.0001] and breast cancer &lt;60 years [8.7 (95% confidence interval, 3.0-25.0); P &lt; 0.0001].
Conclusion: These data may have a significant effect on risk assessment and clinical management of individuals from Denmark who are predisposed to ovarian cancer because they carry a BRCA1 or BRCA2 mutation.