bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2763: Utility of clinical biomarkers for detecting protein kinase CK2 inhibition: A report from the phase I trial of CX-4945
Authors: Lim John K.C. , Padgett Claire S. , Marschke Robert F. , Northfelt Donald W. , Andreopoulou Eleni , Von Hoff Daniel D. , Anderes Kenna , Chen Ta Kung , O'Brien Sean E. 
Published: February 2011

Abstract
Introduction: CX-4945 is a first-in-class, orally administered small molecule that potently and selectively inhibits protein kinase CK2, a previously unexploited molecular target with well documented roles in many cancers. In vitro, CX-4945 selectively kills cancer cells by modulating key survival pathways, resulting in cell cycle arrest, inhibition of cell proliferation, and promotion of apoptosis. CK2 hyperactivation of the PI3K/Akt pathway promotes the phosphorylation of several proteins which we have exploited as biomarkers for CX-4945 activity. A validated laser scanning cytometry method has been developed to quantify the phosphorylation of p21 and Akt in cells, and this has been employed to characterize these substrates in circulating blood cells collected from patients in the phase I clinical trial of CX-4945.
Procedures: Eligible patients with advanced solid tumors with progressive disease, or for whom there are no available standard therapies, were administered CX-4945 in successive dose cohorts using a standard 3×3 design at: 90, 160, 300, 460, and 700 mg per dose. Oral doses were administered twice daily for twenty-one consecutive days of a four week cycle. Serial plasma samples were collected for pharmacokinetic analysis on the first and final dosing days of Cycle 1 (i.e., Day 1 and Day 21). In addition, whole blood samples were collected at pre-treatment, 4 hours and 8 hours following the first dose of CX-4945 on Day 1 and Day 21, and peripheral blood mononuclear cells (PBMCs) were isolated for pharmacodynamic biomarker evaluations (specifically, total and phosphorylated forms of p21 and Akt). Plasma samples were also collected at these time points for quantification of plasma IL-6.
Results: Seventeen patients with advanced solid tumors from five separate dose cohorts have received oral doses of CX-4945 to date, and all patients in the study participated in the collection of PBMCs. Biomarkers from patients in Cohorts 3 and 4 demonstrated changes in their profile consistent with the inhibition of CK2. CX-4945 displays general linearity in PK parameters between the dose cohorts, with a terminal half life of approximately 25 hours at steady state.
Conclusions: To date, no DLTs have yet been observed, and the MTD remains to be defined in this Phase I study. Early signals suggest a modulation of the biomarker profile consistent with CK2 inhibition. Patient enrollment will continue, to further characterize CX-4945's safety, tolerance, pharmacokinetics and pharmacodynamic effects.
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 2763.
Abstract 2764: Genome-wide examination of genetic variants associated with response to platinum-based chemotherapy in patients with small-cell lung cancer
Authors: Wu Chen , Xu Binghe , Yuan Peng , Ott Jurg , Guan Yin , Liu Yu , Shen Yuanyuan , Liu Zhe , Yu Dianke , Lin Dongxin 
Published: February 2011

Abstract
Backgrounds: Small-cell lung cancer (SCLC) accounts for about 20% of total lung cancer and systemic chemotherapy is the major therapy for this cancer. Although most SCLC patients are characterized by initial chemosensitivity to the standard first-line platinum-based regimens, a significant fraction of patients are intrinsic nonresponders. Currently, no reliable biomarkers can be used to predict which patients will respond to platinum-based therapy, and this has inadvertently led to less than optimal treatment of a significant proportion of patients.
Methods: We conducted a genome-wide scan of 440,093 single nucleotide polymorphisms (SNPs) using blood DNAs from 245 SCLC patients treated with the same carboplatin or cisplatin plus etoposide chemotherapy to discover variants associated with response. The results of genome-wide scan were validated in another independent set of 183 SCLC patients.
Results: By Set Association analysis, 20 SNPs were identified associated with treatment response, with odds ratios (OR) ranging from 2.36 (95% confidence interval [CI]=1.56 to 3.57) to 4.38 (95% CI=2.12 to 9.29) and these results were confirmed in the replication phase. Most of these SNPs (14/20) were clustered on chromosomes 22p11.23, 6q24.3, and 20p12.2 where the BTBD3, STXBP5 and BCR genes were located. For example, 85.4% of nonresponders carried the rs41383844 (located downstream of BTBD3) AA genotype whereas 56.4% of responder carried this genotype (OR=5.24, 95% CI=2.47 to 11.13; P=1.63×10−5).
Conclusion: These results suggested that germline genetic variations significantly influence the effectiveness of platinum-based chemotherapy in SCLC patients. Further studies arewarranted to test the value of these findings for personalized chemotherapy.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 2764.
Abstract 2767: Effect of obesity on glutamine levels after L-asparaginase
Authors: Mittelman Steven D. , Hart Nancy , Tom Lana , Nuno Diandra , Butturini Anna 
Published: February 2011

Abstract
L-asparaginase is used as a first-line agent in the treatment of acute lymphoblastic leukemia (ALL). It is believed to act primarily via depletion of the non-essential amino acid asparagine (ASN), since ALL cells are unable to synthesize sufficient ASN to meet their high metabolic demands. However, there is evidence that the depletion of glutamine (GLN) by L-asparaginase might also be important in its anti-leukemia activity.
We have previously shown that children who are obese at the time they are diagnosed with high-risk ALL have a 50% higher chance of relapse. Since adipose tissue is known to produce GLN, the present study was designed to test whether obese subjects diagnosed with high-risk ALL would have less suppression of GLN after an injection of PEG-Asparaginase than their lean counterparts.
Four lean (BMI 35 ± 19 %ile, 2 male/2 female) and 3 obese (BMI 98 ± 1 %ile, 2 male/1 female) adolescents with new diagnosis of high-risk ALL were studied so far. Amino acid levels were measured by HPLC in the CHLA clinical laboratory prior to and at weekly interval after injection of PEG-Asparaginase (2500 IU/m2). One lean subject received the drug intravenously, the remainder intra-muscularly. The other drugs used in induction were vincristine, daunomycin and prednisone, per CCG 1961 protocol, not on study. No dose adjustments were made based on obesity.
Prior to treatment, there were no differences in plasma ASN (44.3±17.2 vs. 42.5±17.3 μM obese vs. lean, p=0.90) or GLN (539±78 vs. 567±247 μM, obese vs. lean, p=0.85) levels between groups. Two weeks after treatment, ASN levels were suppressed to ≤2 μM in both groups. In contrast, GLN levels after PEG-Asparaginase were different in obese vs. lean patients: in the obese patients, GNL level significantly increased by the second week after treatment (709±111 μM, p=0.02 vs. week 0) while no significant changes were detected in lean subjects (509±141 μM, p=0.36 vs. week 0). The change in GLN level from week 0 to 2 was +170±43 and −58±107 μM in obese and lean subjects, respectively (p=0.02).
Thus, obesity appears to affect GLN levels after a single injection of PEG-Asparaginase. The differences in plasma GLN levels might reflect larger differences in GLN levels in the local leukemia microenvironment (e.g. bone marrow, adipose tissue). Although the clinical significance of this observation is limited by the small patient sample, these data highlight the need for further studies to investigate the role of obesity on the efficacies of chemotherapies.
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 2767.
Abstract 277: Downregulation of the receptor tyrosine kinase cMet is impaired in pancreatic adenocarcinoma cells
Authors: Hill Kristen S. , Lorinczi Marta , Elferink Lisa A. 
Published: February 2011

Abstract
Increased signaling from cMet, the receptor for Hepatocyte Growth Factor (HGF) has been implicated in the progression of many cancers, particularly pancreatic cancer, correlating with cellular transformation, tumor invasion and poor patient prognosis. In contrast to other cancers, receptor mutations that result in increased cMet signaling have yet to be detected in pancreatic cancers. This led us to hypothesize that post translational mechanisms such as impaired cMet down regulation, a process that normally functions to attenuate cMet signaling in vivo, could be a factor for increased cMet signaling in pancreatic tumors. To test this, we examined the lysosomal down regulation of cMet in a panel of pancreatic adenocarcinoma cell lines. Here we report that uncoupled cMet down regulation in pancreatic tumor cells correlates with increased cMet stability and signaling in response to HGF. In pancreatic Suit-2 cells, impaired binding of the E3 ubiquitin ligase Cbl to cMet, results in reduced receptor ubiquitination and increased cMet recycling to the cell surface. Conversely, transient HGF induced cMet ubiquitination in pancreatic BxPC-3 cells correlates with prolonged cMet stability and signaling, suggesting that the kinetics of cMet ubiquitination rather than receptor ubiquitination per se is critical for efficient cMet down regulation. These data mark the first evidence that disrupted cMet down regulation could be a contributing factor in the aggressiveness of certain pancreatic tumor cells and highlights the importance of the endocytic machinery as a novel therapeutic target.
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 277.
Abstract 2778: Association between mammographic density and serum 25-hydroxyvitamin D levels
Authors: Crew Katherine D. , Flom Julie , Tehranifar Parisa , Terry Mary Beth 
Published: February 2011

Abstract
Background: Previous studies have demonstrated an inverse association between vitamin D and risk of breast cancer. In addition, dietary vitamin D intake has been associated with lower mammographic density (MD), a strong intermediate marker of breast cancer risk. We examined the relationship between MD and serum 25-hydroxyvitamin D [25(OH)D], an integrated measure of vitamin D status from food, supplements, and sun exposure, in a multi-ethnic cohort of women undergoing screening mammography.
Methods: Using a cross-sectional study design, 195 women without a history of breast cancer completed a routine screening mammogram, in-person interviews collecting data on demographics, lifestyle factors, and breast cancer risk factors, and donated a blood sample. We digitized mammograms and evaluated the proportion of dense area on cranial-caudal images using Cumulus software. Serum 25(OH)D was measured in batched, archived specimens by Diasorin radioimmunoassay. We used a multivariate linear regression model to investigate the association of percent density with serum 25(OH)D. We examined confounding by age, race/ethnicity, body mass index (BMI), season of blood draw, and breast cancer risk factors.
Results: A total of 195 women enrolled, 116 donated a blood sample and were evaluable for analysis; median age: 49.9 years (range 40.0-60.9); white/African American/African Caribbean/Hispanic Caribbean: 26%/43%/19%/12%. The prevalence of vitamin D deficiency [25(OH)D &lt;20 ng/ml] was 24% among whites, 52% in African Americans, 33% in African Caribbeans, and 43% in Hispanics (Chi-square p-value=.09). Age and BMI were inversely associated with MD (p&lt;0.001). After adjusting for known confounders, we found no association between serum 25(OH)D and percent density.
Discussion: In contrast to some previous reports, vitamin D does not appear to be related to MD in this multiethnic cohort. Vitamin D status, a potentially modifiable risk factor, may have a protective effect against breast cancer development which is not mediated by changes in breast density.
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 2778.
Abstract 2789: C-reactive protein and risk of lung cancer
Authors: Chaturvedi Anil , Caporaso Neil , Katki Hormuzd , Wong Hui-Lee , Chatterjee Nilanjan , Pine Sharon , Chanock Stephen , Goedert James , Engels Eric 
Published: February 2011

Abstract
Background: Chronic inflammation could act as a co-factor to tobacco smoke in increasing lung cancer risk, underscoring the potential for both lung cancer prevention and screening. We investigated the association of circulating high-sensitivity C-reactive protein (CRP) and CRP single nucleotide polymorphisms (SNPs) with prospective risk of lung cancer.
Methods: We conducted a nested case-control study of 592 lung cancers and 670 controls with available pre-diagnostic serum and 378 cases and 447 controls with available DNA within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N=77,464). Controls were matched to cases on age, sex, entry year, follow-up time, and smoking status (cumulative amount and time since quitting). We measured CRP levels in baseline serum samples and genotyped 5 common CRP SNPs.
Results: Elevated CRP levels were associated with increased lung cancer risk (odds ratio [OR] for individuals in the fourth quartile (Q4, ≥5.6 mg/L) vs. those in Q1 (&lt;1.0 mg/L)=1.98; 95% CI=1.35-2.89), with a trend for increasing risk across CRP quartiles (p-trend&lt;0.001). This association was most apparent for squamous cell carcinomas (OR=2.92; 95% CI=1.30-6.54), in the 2-5 years before lung cancer diagnosis (OR=2.33; 95% CI=1.24-4.39), and among former (OR=2.48; 95% CI=1.53-4.03) and current smokers (OR=1.90; 95% CI=1.06-3.41). Although CRP SNPs and haplotypes were associated with significant differences in CRP levels, they were not associated with lung cancer risk. Ten-year standardized absolute risks of lung cancer were higher with elevated CRP levels, among both former (Q4=2.55% vs. Q1=1.39%) and current smokers (Q4=7.37% vs. Q1=4.03%).
Conclusions: Elevated CRP levels are associated with subsequently increased lung cancer risk, in support of an etiologic role for chronic pulmonary inflammation in lung carcinogenesis. The separation in lung cancer absolute risks across circulating CRP levels among former and current smokers provides preliminary evidence for the utility of CRP measurements in lung cancer risk stratification.
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 2789.
Abstract 2791: Blood C-reactive protein levels and colon cancer risk
Authors: Yang Gong , Chow Wong-Ho , Shu Xiao-Ou , Li Honglan , Xiang Yongbing , Wen Wanqing , Ji Butian , Rothman Nathaniel , Zhang Xianglan , Cai Qiuyin , Gao Yu-Tang , Zheng Wei 
Published: February 2011

Abstract
Background: Circulating C-reactive protein (CRP), a sensitive marker of low-grade systemic inflammation, has been associated with an increased risk of colon cancer in some but not all studies. Few studies have evaluated the association by the time interval between blood collection and cancer diagnosis.
Objective: To prospectively evaluate the association between blood CRP levels and colon cancer risk, as well as the potential effect of time window of CRP measures on the association.
Design: A nested case-control study of 209 cases of colon cancer and 279 controls identified from the Shanghai Women's Health Study with up to 10 years of follow-up. Conditional logistic regression was used to estimate odds ratios (OR) of developing colon cancer and their 95% confidence intervals (CI) associated with blood CRP levels.
Results: Blood CRP levels were positively associated with colon cancer risk (P trend = 0.003). Women in the highest quartile of CRP had an adjusted OR of 2.52 (95% CI: 1.36 − 4.70) compared with women in the lowest quartile. The risk was higher for women whose CRP was measured in blood collected ≤5 years prior to diagnosis (OR for the highest quartile of CRP = 3.67; 95% CI: 1.41 − 9.56; P for trend = 0.006), compared to women with samples collected &gt;5 years before diagnosis (corresponding OR = 1.98; 95% CI: 0.83 − 4.74; P for trend = 0.15).
Conclusion: Our findings support the hypothesis that low-grade systemic inflammation is associated with an increased risk of colon cancer. Cancer-induced inflammation may partly explain the observed association.
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 2791.
Abstract 2792: Serum vitamin D and colorectal cancer risk in a large male cohort
Authors: Weinstein Stephanie J. , Yu Kai , Horst Ronald , Virtamo Jarmo , Albanes Demetrius 
Published: February 2011

Abstract
Only a few studies have prospectively evaluated biologic measures of vitamin D in relation to colorectal cancer risk, with some suggesting an inverse association, although inconsistencies remain. The accepted biomarker of vitamin D status, 25-hydroxyvitamin D [25(OH)D], integrates total vitamin D intake and vitamin D synthesized as a result of UVB exposure from sunlight. We conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men based on 239 colon and 192 rectal cancer cases, along with an equal number of controls matched on age (+/- 1 year) and date of blood draw (+/-30 days). Baseline serum samples were assayed for 25(OH)D using the DiaSorin LIAISON 25(OH)D TOTAL assay, with interbatch and intrabatch CVs of 12.3% and 10.5%, respectively. Conditional logistic regression models provided odds ratios (OR) and 95% confidence intervals (CI) for the association between 25(OH)D and colon and rectal cancers separately, adjusted for years of smoking and serum α-tocopherol, β-carotene, and retinol (and conditioned on the matching factors). 25(OH)D concentrations were categorized using clinically defined cutpoints of &lt;25, 25 to &lt;37.5, 37.5 to &lt;50, 50 to &lt;75 (referent), and &gt; 75 nmol/L. Both colon and rectal cancer cases had non-significantly higher 25(OH)D concentrations compared with controls (p=0.14 and 0.63, respectively). We observed no inverse association between 25(OH)D and colon or rectal cancer (Table). Patterns in risk did not differ by season of blood draw or time from blood draw to diagnosis. Additional analyses with 25(OH)D residually-adjusted for season and with season-specific cutpoints were similarly null. In our study, few subjects had high (&gt; 75 nmol/L) 25(OH)D, which may account for our finding no evidence of serum 25(OH)D being prospectively associated with colon or rectal cancer risk.ORs and 95% CIs for the association between serum 25(OH)D and risk of colon and rectal cancersSerum 25(OH)D (nmol/L)ColonRectum Cases/ControlsOR (95% CI)Cases/ControlsOR (05% CI)&lt;25.077/870.63 (0.36-1.12)68/700.62 (0.33-1.18)25.0 - &lt;37.563/600.91 (0.52-1.59)42/460.56 (0.27-1.13)37.5 - &lt;50.040/440.73 (0.39-1.36)33/330.82 (0.39-1.71)50.0 - &lt;75.047/401.00 (reference)39/321.00 (reference)≥75.012/81.44 (0.49-4.26)10/110.62 (0.22-1.76)P trend 0.11 0.23
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 2792.
Abstract 2799: Serum vitamin D and risk of bladder cancer in the ATBC Study
Authors: Mondul Alison M. , Weinstein Stephanie J. , Mannisto Satu , Virtamo Jarmo , Albanes Demetrius 
Published: February 2011

Abstract
Background: Urinary bladder cancer is an important health concern in developed countries, particularly for men, among whom incidence is 3-5 times greater than in women. Vitamin D is thought to protect against cancer at many sites. However, to our knowledge, no studies have examined the association between serum vitamin D and bladder cancer.
Methods: Within the ATBC Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and β-carotene supplements on cancer incidence, 250 bladder cancer cases were randomly sampled by month of blood collection such that there were 25 cases included from each month with 25 cases total from June - August because fewer blood collections were conducted during the summer months. Controls were sampled from ATBC study participants who were alive and cancer free at the time the case was diagnosed and were matched 1:1 with cases on age at randomization (± 1 year) and date of blood collection (± 30 days). Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals of bladder cancer by a priori categories of baseline serum 25-hydroxy vitamin D (&lt;25, 25 - &lt;37.5, 37.5 - &lt;50, ≥ 50 nmol/L).
Results: After multivariable adjustment, lower serum vitamin D was associated with a statistically significantly increased risk of bladder cancer (OR, 95% CI vs. ≥ 50 nmol/L; 37.5 - &lt;50 nmol/L: 2.04, 1.13 − 3.70; 25 - &lt;37.5 nmol/L: 1.90, 1.07 − 3.35; &lt;25 nmol/L: 1.83, 1.06 − 3.14; p-trend = 0.03), although the risk did not appear to increase with progressively lower vitamin D levels. Rather, men in any category of serum vitamin D below 50 nmol/L were at approximately two-fold risk compared to men with serum vitamin D ≥50 nmol/L (OR, 95% CI: 1.91, 1.20 − 3.04; p value = 0.006). Although the results were not statistically significant, there was a suggestion that the vitamin D - bladder cancer association was stronger among men who smoked less, were not assigned to the α-tocopherol intervention arm, or whose blood samples were obtained during the sunnier months.
Conclusion: In this population of male smokers, lower vitamin D was associated with an increased risk of bladder cancer. Future studies should examine this association in other populations, especially women and non-smokers. Replication in a larger sample may clarify possible subtle effect modification by smoking, season, and intake of other nutrients.
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 2799.