bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 167: Identification of differentially methylated genes in normal prostate tissues from African American and Caucasian men
Authors: Kwabi-Addo Bernard , Wang Songping , Lee Norman H. , Estecio Marcos R. , Jelinek Jaroslav , Chung Woonbok , Ittmann Michael M. 
Published: February 2011

Abstract
BACKGROUND. Prostate cancer (PCa) is a common malignancy and a leading cause of cancer deaths among men in the United States. African American men have both a higher incidence and significantly higher mortality rates than Caucasian men. Abundant evidence has accumulated to suggest that epigenetic DNA methylation changes may appear earlier during PCa development than genetic changes, as well as more commonly and consistently. Most studies have emphasized DNA hypermethylation as an important mechanism for inactivation of key regulatory genes in prostate cancers. Thus methylated genes can serve as biomarkers for the detection of cancer from clinical specimens such as tissue biopsies or body fluids. However, very few studies have investigated differences in DNA methylation pattern in different ethnic groups or their application as ethnic sensitive biomarkers for disease detection. We hypothesize that differential methylation patterns maybe associated with ethnicity and could potentially contribute to the incidence and mortality of prostate cancer. METHODS. We have identified several genes to be differentially methylated in human prostate cancer cell line using methylated CpG island amplification coupled with CpG promoter microarray. Pyrosequencing was used to quantitatively measure the methylation levels of CDH11, FOXN4, PAX9, TIMP3, RPRM, SPARC, TCF3,CYP27B1, RARβ2, AR, GSTP1, NKX2-5, RASSF1A and TIMP3 genes in prostate cell lines, matched pairs of benign and prostate cancer tissues from individual prostate cancer patients, and normal prostate biopsies from African American and Caucasian men. Real time PCR was used to determine gene expression at the RNA transcript level. RESULTS. DNA hypermethylation was observed for NKX2-5, FOXN4, TIMP3, RPRM, TCF, SPARC, GSTP1, RASSF1A, RARβ2 and SPARC in prostate cancer cells and prostate cancer tissues samples. Higher frequency of methylation was observed for several genes including NKX2-5, GSTP1, RASSF1A, and RARβ2 genes in punch biopsies of normal prostate samples obtained from African American men in comparison to samples from Caucasian men. CONCLUSION. Our observations suggest a genome wide differential methylation patterns in prostate tissue samples obtained from African American men versus Caucasian men. Such alterations could account for some of the biological differences underlying prostate cancer disparity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 167.
Abstract 1672: The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates
Authors: Kim AeRang , McCully Cindy , Cruz Rafael , Cole Diane E. , Fox Elizabeth , Balis Frank M. , Widemann Brigitte C. 
Published: February 2011

Abstract
Background: Sorafenib is an oral multikinase inhibitor that targets intracellular and receptor protein kinases thought to be crucial in the pathogenesis and growth of many tumors including brain tumors. Sorafenib is FDA approved for advanced renal cell and hepatocellular carcinoma. Clinical trials in primary and metastatic brain tumors are ongoing. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of sorafenib after an intravenous (IV) dose in a non-human primate (NHP) model. Methods: Sorafenib 7.3 mg free base equivalent/kg was administered as a 1h IV infusion in 20% cyclodextrin and normal saline to 3 NHP with IV catheters and Ommaya reservoirs. Serial paired plasma and CSF samples were drawn over 24h for PK analysis. Sorafenib was quantified with a validated liquid chromatography/tandem mass spectrometry assay. The lower limit of quantification for plasma and CSF was 5 ng/mL and 0.025 ng/mL, respectively. PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUC CSF : AUC plasma. Plasma free drug exposures (AUC) were calculated from published values for human plasma protein binding (99.5%). Results: IV administration of sorafenib was well tolerated in the NHP without evidence of clinical toxicity. The PK parameters of sorafenib in NHP for plasma and CSF are described in the table below. The mean CSF penetration of sorafenib was 0.02%. When corrected for plasma protein binding, the mean CSF penetration was 3.4%. Conclusions: Sorafenib is well tolerated in NHP and measureable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma.Plasma and CSF PK of sorafenib in NHPAnimalCmax plasma [µg/mL]Clearance [mL/min/kg]AUC 0-24h plasma [µg•h/mL]Cmax CSF [µg/mL]AUC 0-24h CSF [µg•h/mL]CSF penetration [%]17.62.231.20.000450.00420.01326.42.029.60.000580.00660.02233.41.323.20.000460.00340.015Mean5.81.728.00.000500.00480.02SD2.10.54.30.000070.00160.005
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1672.
Abstract 1673: A pharmacokinetics/pharmacodynamics evaluation of the concentration-QTc relationship of PF-02341066 (PF-1066), an ALK and c-MET/HGFR dual inhibitor administered orally to patients with advanced cancer
Authors: Nickens Dana , Tan Weiwei , Wilner Keith , Camidge D. Ross , Shapiro Geoffrey , Dezube Bruce , Clark Jeffrey 
Published: February 2011

Abstract
Objective: Assess the potential effect of PF-1066 plasma concentrations on the observed RR corrected QT interval in patients with advanced cancer.
Methods: Plasma concentrations of PF-1066 (total drug) and ECG data were collected in study A8081001, an open label, multi-center Phase 1 dose escalation, and safety, pharmacokinetic and exploratory study (J Clin Oncol 27:15s, 2009 (suppl; abstr 3509)). PF-1066 was administered orally on an empty stomach once (QD) or twice (BID) a day in continuous 28-day cycles with doses ranging from 50 mg QD to 300 mg BID. Time-matched, triplicate (≥ 2 minutes apart) ECGs were obtained during the screening period, at pre-dose, 6 hours (∼ Cmax), and 24 hours post-dose on Cycle 1 Day 1, and at pre-dose and 6 hours (∼ Cmax) post-dose on Cycle 1 Day 15 and Cycle 2 Day 1. Baseline ECG data was used to assess which heart rate correction method (QTcB, QTcF and a study specific correction, QTcS) was most appropriate. A linear mixed effects model was used to evaluate the relationship between plasma concentrations and the RR-interval and corrected QT-interval.
Results: A total of 62 patients were available for this analysis. The majority of patients had at least 5 triplicate measurements post dose. Fifty-three percent (n=33) were male. Plasma concentrations ranged from 0.228 ng/mL to 1040 ng/mL and the median concentration over all doses was 83.2 ng/mL. At baseline, median heart rate, QTcB- and QTcF-interval were, respectively, 80 bpm, 429 msec and 408 msec. The post-treatment median heart rate, QTcB- and QTcF-interval were, respectively, 73 bpm, 432 msec and 416 msec. The concentration-RR analysis indicates that on average heart rate decreases at approximately 2.5 bpm per 100 ng/mL increase in PF-1066 concentration. QTcS was determined as the most appropriate heart rate correction method for QT-interval. The estimated slope for concentration-QTcS-interval is 0.0076 msec/ng/mL (90% conf. limits: −0.0051, 0203), indicating a small but not statistically significant positive trend in the concentration-QTcS relationship. Based on the model, the average drug associated increase in QTcS is 2.9 msec at the mean Cmax following 250 mg BID dosing.
Conclusion: Based on the PK/PD analysis, a clinically relevant QT prolongation is not expected within the therapeutic dose range (up to 250 mg BID) of PF-1066 in patients with advanced cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1673.
Abstract 1674: The NQO1 C609T polymorphism is associated with poorer response to AC adjuvant therapy in the treatment of breast cancer
Authors: Jamieson David , Cresti Nicola , Bray Johanne , Sludden Julieann , Griffin Melanie , Farmie Eve , Verrill Mark , Boddy Alan 
Published: February 2011

Abstract
A non-synonymous SNP in the NAD(P)H: Quinone Oxidoreductase 1 gene has previously been implicated in the response of breast cancer patients to anthracycline containing regimens in a retrospective cohort study. NQO2 is 54% homologous to NQO1 at the primary protein structure and, despite the lack of a characterised endogenous electron donating cofactor for NQO2, the two enzymes share numerous substrates. NQO2, in contrast to NQO1, is additionally capable of reducing reactive quinone metabolites of estradiol. The NQO2 gene has a non-synonymous SNP that has previously been shown to result in a lower average NQO2 activity in cohorts of bladder and ovarian cancer patients. It is unknown if the NQO2 SNP impacts on survival in breast cancer.
Genomic DNA samples from 239 women with early breast cancer were genotyped for the NQO1 (rs1800566) and NQO2 (rs1143684) SNPs. All of the participants were recruited from Medical Oncology out-patient clinics within the Newcastle upon Tyne Hospitals NHS Foundation Trust and were treated with an AC adjuvant therapy regimen with curative intent. Median follow up was 78 months and followed a standard protocol. Genotyping was done by the Taqman RT-PCR method.
The NQO1 SNP was associated with a decreased time to progression (HR 2.8, 95%CI 1.4-5.64, p=0.003), decreased overall survival (HR 3.6, 95%CI 1.4-10, p=0.007) and a lower likelihood of having a dose delay, all indicative of NQO1 mediated sensitisation to the effects of doxorubicin. The NQO2 SNP had no impact on the cohort as a whole but was associated with a decreased overall survival (p=0.009, log-rank) and time to progression (p=0.004, log rank) in patients who were oestrogen receptor (ER) negative.
This study confirms the previous observation of NQO1 genotype influencing response to anthracyclines and indicates a potential impact of an NQO2 SNP on the prognosis of ER negative breast cancer. The mechanism by which NQO2 genotype influences breast survival remains to be elucidated.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1674.
Abstract 1686: Low dose metronomic gemcitabine has high antimetastatic efficacy in an orthotopic mouse model of pancreatic cancer
Authors: Cao Hop S. Tran , Bouvet Michael , Romney Eric , Kaushal Sharmeela , Keleman Alex , Kim Ginna , Fruehauf John , Imagawa David K. , Hoffman Robert M. , Katz Matthew H.G. 
Published: February 2011

Abstract
Therapies for metastasis of pancreatic cancer (PC) are ineffective. We report here the efficacy of metronomic gemcitabine with and without the tyrosine kinase inhibitor sunitinib (SU) on metastasis in an orthotopic model of PC.
Mice with highly metastatic, orthotopic PC expressing red fluorescent protein (RFP) were treated with intraperitoneal gemcitabine on a metronomic (1 mg/kg daily, MET) or with maximum tolerated dose (150 mg/kg twice weekly, MTD) schedule with or without oral SU. Primary tumor growth, metastasis, and survival were evaluated. Primary tumor growth and metastasis were quantified by fluorescence imaging.
Control mice with orthotopically-implanted MIA-PaCa-2-RFP died of local and widespread metastatic disease within 4 weeks. Gemcitabine at daily doses of 2 mg or greater led to toxicity and death within 1 month in mice without tumors but MET at 1 mg/kg daily was well tolerated. Treatment of mice with orthotopic MIA-PaCa-2-RFP with MET at 1 mg/kg daily for 2 weeks dramatically suppressed metastasis at multiple sites_an effect enhanced by SU (p&lt;0.05). Although primary tumor growth was inhibited by MET+SU (p&lt;0.05), it was not inhibited by either MET or SU alone. Both MET and SU had a modest effect on survival compared to control but survival was limited by extensive primary tumor growth. MET+SU had a more pronounced effect on survival (p&lt;0.05). MTD with or without SU had the most pronounced effects on primary tumor growth and survival but its antimetastatic effect was similar to that of MET+SU (p&lt;0.05). Antimetastatic activity approaching that of standard MTD gemcitabine was achieved with a gemcitabine dose reduced 42 times from MTD using MET and was further enhanced by sunitinib. Our results suggest the clinical potential of this well-tolerated regimen of MET against PC in the adjuvant and maintenance settings.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1686.
Abstract 169: The origin of colorectal cancer with CpG island methylator phenotype
Authors: Toyota Minoru , Yamamoto Eiichiro , Suzuki Hiromu , Kamimae Seiko , Yamano Hiro-o , Shinomura Yasuhisa , Imai Kohzoh 
Published: February 2011

Abstract
Colorectal cancers (CRCs) are divided into three different subclasses based on the genetic and epigenetic profiles: CpG island methylator phenotype (CIMP) 1, CIMP2 and CIMP-negative. CIMP1 has been shown to be associated with BRAF mutations and sessile serrated adenoma. CIMP2 has been shown to be associated with KRAS mutation, but precursor lesions of CIMP2 remain to be determined. Our aim of this study is to identify the origin of CRCs with CIMP by examining the promoter methylation of tumor-related genes and genome-wide methylation profiles in precursor lesions. Based on histological examination after endoscopic mucosal resection or operation, the specimens were divided into two groups: 65 serrated polyps (SPs), 109 colon adenomas (ADs) with or without high grade dysplasia. Endoscopically, subsets of SPs were composed of flat and protruded lesions, and biopsy samples were obtained from both lesions, and were divided into three groups: flat lesions only (SP1, 19 cases), flat lesions adjacent to protruded lesions (SP2, 21 cases), or protruded lesions adjacent to flat lesions (SP3, 25 cases). Mutations of BRAF were observed frequently in SPs but not in ADs (26% vs 2%), indicating that the SPs are the origin of CIMP1 characterized by BRAF mutations and microsatellite instability as suggested previously. Frequencies of KRAS mutations were highest in tubulovillous adenomas (TVs) followed by SPs, and tubular adenomas (TAs) (57% vs 43% vs 20%). High frequency of KRAS mutations in SPs and TVs prompt us to examine genome-wide methylation profiles in these tumors. By hierarchical clustering analysis of the MCAM results, SP3, SP1/SP2, and normal colon were grouped into three distinct clusters, and it is suggested that genome-wide methylation occurs during the course of progression from SP2 to SP3, and was associated with acquirement of CIMP. We further examined methylation profiles of additional SPs, ADs (TVs and TAs) with KRAS mutations. Cluster analysis of KRAS mutant SPs and ADs grouped tumors into three clusters; cluster-1 with genome-wide aberrant methylation, cluster-2 with moderate methylation, and cluster-3 with little methylation. Cluster-1 contained SP3 and majority of TVs, cluster-2 contained SP1, SP2, and TAs, and cluster-3 contained normal colon. The present study suggested that CRCs with CIMP2 are originated from two distinct subgroups; CIMP2-protruded (CIMP2-P) originated from serrated-villous protruded tumors, and CIMP2-depressed (CIMP2-D) originated from tubular-depressed pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 169.
Abstract 170: Hypermethylation of DBCCR1 gene in acute myeloid leukemia
Authors: Dai Aili , Zhao Chen , Yin C. Cameron , Chen Ling , Sun Xiaoping , Dave Sanat , Huang Xiaoyan , Zhang Yu H. , Han Xin , You M. James 
Published: February 2011

Abstract
DNA hypermethylation likely plays a role in the tumorigenesis and prognosis of acute myeloid leukemia (AML). To identify relevant methylated genes in AML, we have compared several expression and methylation profiles. With expression analysis, we identified that DBCCR1, TRPC6, DCC and SOX9 have decreased expression levels in the most analyzed AML cell lines. Among these candidates, DBCCR1 (deleted in bladder cancer chromosomal region candidate 1) gene at chromosome 9q33 was identified as a putative tumor suppressor gene that is frequently targeted by hypermethylation in transitional cell carcinomas of the bladder. In addition, DBCCR1 was reported frequently methylated in hematological malignancies, including diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. DBCCR1 may play an important role in the regulation of cell growth and programmed cell death. But the expression levels and methylation status of DBCCR1 in AML have not been established. In this study, we analyzed the expression pattern of DBCCR1 in AML cell lines with RT-PCR analysis. DBCCR1 mRNA expression was robust in normal bone-marrow mononucleated cells but markedly diminished in all of 9 AML cell lines. DBCCR1 was methylated in all of AML cell lines (9 of 9, 100%) and its methylation was inversely correlated with DBCCR1 mRNA expression, which was demonstrated by RT-PCR and COBRA (Combined Bisulfite Restriction Analysis) analyses. Furthermore, we also detected frequent methylation (at least 90%) of DBCCR1 in multiple primary AML samples. These findings indicate that DBCCR1 is frequently silenced by hypermethylation in AML. We are investigating the functional role of DBCCR1 in the pathogenesis of AML. In addition, the diagnostic and prognostic values of methylated DBCCR1 in AML are being pursued. In summary, putative tumor suppressor gene DBCCR1 shows significantly diminished expression in AML due to frequent hypermethylation.
* Aili Dai and Chen Zhao contributed equally to the presented work.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 170.
Abstract 1700: An improved synthesis and mutagenicity studies of O2-[4-(3-pyridyl-4-oxobut-1-yl]thymidine, the major adduct formed by tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in vivo
Authors: Gowdahalli Krishnegowda , Sharma Arun K. , Krzeminski Jacek , Desai Dhimant , Lin Jyh-Ming , Gowda A.S. Prakasha , Spratt Thomas E. , Amin Shantu 
Published: February 2011

Abstract
Among the four pyridyloxobutyl (POB)-DNA adducts formed in the lung and liver of rats treated with tobacco specific nitrosamines [N′-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)], the O2-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine (O2-POB-dThd) has been found to be the most persistent. It is an important biomarker to assess the human exposure to these carcinogens and also serves as a useful precursor for the synthesis of site-specifically modified oligomers required for mutagenicity studies. The only synthetic method reported for O2-POB-dThd requires repeated HPLC purifications and could only be used to prepare an analytical standard due to very low yield (0.4%). Our continued efforts have now led to the development of an efficient method for the total synthesis of O2-POB-dThd and its site-specifically adducted oligonucleotides. The synthesis of O2-POB-dThd was achieved by optimizing reaction between O2-5′-anhydrothymidine and sodium salt of 4-(1,3-dithian-2-yl)-4-(3-pyridyl)butan-1-ol, followed by deprotection of the dithiane group. The product was characterized by NMR (1H, 13C, and COSY spectra), MS, and HPLC analysis. This synthetic strategy provided for the first time a reliable method for a gram scale total synthesis of O2-POB-dThd that allowed for solid state site-specifically adducted oligomer synthesis. O2-POB-dThd was converted to its phosphoramidite and subsequently used for the synthesis of the oligomer by standard methods. The oligomer was characterized by MS and HPLC analysis. We examined the in vitro kinetics of the synthesized oligomer with the Klenow fragment of E. Coli DNA polymerase I with the exonuclease activity inactivated (Kf(exo-)) and human DNA polymerasesl eta, kappa, and iota). O2-POB-dThd was replicated in a mutagenic manner with with Kf(exo-)and human pol eta and was unreactive with pol kappa and iota. In summary, highly facile syntheses of O2-POB-dThd and its site-specifically adducted oligonucleotide are developed. The study will facilitate elucidation of mechanistic aspects and mutagenic potential of O2-POB-dThd adduct, and will provide further insight into the role it plays in inducing cancers in smokers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1700.