bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B71: Segmental analysis of colorectal cancer in California by race/ethnicity, 2001–2008
Authors: Cho Myung Mi , Nagavedu Kshema , Chenna Sumana , Morgan John W. 
Published: June 2012

Abstract
Purpose: This study seeks to identify the independent predictive roles of selected demographic variables for invasive colorectal cancer (CRC) sub-sites.
Methods: Demographic and sub-site variables were extracted from the California Cancer Registry (CCR) for 117,354 invasive colon cancer cases diagnosed from 2001–2008. Stratified and Logistic regression analyses were used to distinguish individual predictive effects of demographic variables on odds of CRC in contrasting bowel segments.
Results: Multivariable odds ratios (OR) for binary bowel segment categories contrasting &lt;40 (OR =1.20; 95% CI =1.11-1.30), 40–49 (1.48; 95% =1.41-1.55) and 75+ (0.54; 0.53–0.56) relative to age 50–74 years reveal independent associations. Contrast with non-Hispanic white, ORs for left to non-left bowel cancer were 1.68; 95% CI =1.56-1.81 (Asian/Other), 0.73; 0.62–0.84 (non-Hispanic black) and 1.12; 1.01–1.24 (Hispanic). Females showed lower odds of left to non-left bowel cancer than males (OR =0.75 CI =0.73-0.77). Descending ORs were seen for sequentially lower SES quintiles (OR1:5 = 1.11; 1.05–1.17, OR2:5 = 1.07; 1.02–1.12, OR3:5 = 1.02; 0.978–1.06 and OR4:5 = 0.98; 0.94–1.02) (Trend p &lt;0.0001) adjusting for other covariates. No significant multiplicative interaction was detected between race/ethnicity and SES variables. Findings were similar for contrasts of distal to non-distal and sigmoid colon to non-sigmoid CRC.
Conclusions: Younger than age 50–74; male gender; Asian/Other or Hispanic ethnicity, and lower SES were each independent predictors of left to non-left CRC. Progressively lower SES showed an inverse dose-response relationship with odds of left to non-left CRC, independent of other covariates. These findings reveal demographic predictors of CRC bowel segment origin that may influence screening success.
Funding: The California Department of Public Health, National Cancer Institute (Grant N01-PC-35136 and N01-PC-35139), and Centers for Disease Control & Prevention (CDC) (Grant N02-PC-54404) funded cancer surveillance necessary for this study.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B71.
Abstract B96: Trends in colorectal cancer screening with home-based fecal occult blood test (FOBT) in adults aged 50–64 years, 2000–2008
Authors: Bandi Priti , Cokkinides Vilma , Smith Robert A. , Jemal Ahmedin 
Published: June 2012

Abstract
Introduction: Screening for colorectal cancer (CRC) in asymptomatic average risk populations reduces CRC incidence and mortality. Annual home-based fecal occult blood testing (FOBT) has been recommended as a CRC screening modality in average-risk adults aged 50 and older. National surveys have reported declines in FOBT screening rates in the last decade, but it is unknown whether these declines have extended across all socioeconomic status (SES) and racial/ethnic groups, and the changes relative to endoscopic screening have not been evaluated.
Methods: Data on respondents aged 50–64 years were from the Cancer Control Module administered to sampled adults National Health Interview Surveys in 2000, 2005, and 2008. Weighted analyses and multivariate logistic regression were used to study trends in the use of home FOBT testing in the past year and endoscopic test in the past 10 years.
Results: Overall, the prevalence of home FOBT in the past year declined 5.9% points (95% CI: 4.5%, 7.3%) between 2000 and 2008. SES differences in trends were observed wherein significant declines were restricted to higher-SES groups (those with private and military insurance, those with a usual source of care, those with a high school degree or higher, those classified as not poor, those born in the US), whereas lower-SES (uninsured and the publicly-insured, those without a usual source of care, those with less than a high school education, the poor and the near poor, and immigrants to the US) did not experience significant changes in FOBT prevalence during this time period. FOBT rates in Hispanics did not change significantly during this time, whereas non-Hispanic whites and non-Hispanic blacks experienced significant declines. Coincident with declines in FOBT prevalence during this time, endoscopic screening prevalence increased consistently in higher-SES groups. Fewer lower-SES groups experienced increases in endoscopic screening prevalence, with most increases being of a lower magnitude than in the higher-SES subgroups.
Conclusions: Socially and economically disadvantaged groups experienced little or no change in FOBT rates from 2000 to 2008. There has been a significant shift from FOBT to endoscopic screening in higher-SES and a few lower-SES groups, but the extent of this shift in lower-SES groups appeared to be smaller than in higher-SES groups. Programs promoting annual screening with high-sensitivity guaiac-based or immunochemical FOBT represent an appropriate and low cost alternative to colonosopy screening, provided that these programs consider patient- and physician attitudes, knowledge and preferences, and systems-issues related to referral, adherence, test quality assurance, and adequate follow-up of positive test results.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B96.
Abstract ED02-02: How we measure and track health disparities in the Healthy People 2010 Final Review
Authors: Talih Makram 
Published: June 2012

Abstract
The Healthy People 2010 Final Review presents a quantitative end-of-decade assessment of progress in achieving the Healthy People 2010 objectives and goals over the course of the decade. It provides the most recent tracking data available on or before March 1, 2011, for the 970 objectives in each of the 28 Healthy People 2010 Focus Areas. We will describe the procedures used to measure disparities among population subgroups in connection with the second goal of Healthy People 2010, which is to “eliminate health disparities.” We will discuss methodological issues that arise in the selection of the best group rate, as well as in the definition of a summary (or average) index of disparities. Those considerations impact how changes in disparities over time are ascertained.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):ED02-02.
Abstract A115: Contextual synthetic lethality: Repair-deficient hypoxic tumor cells are sensitized to poly(ADP-ribose) polymerase (PARP) inhibition
Authors: Chan Norman , Pires Isabel M. , Bencokova Zuzana , Coackley Carla , Bhogal Nirmal , Lakshman Minalini , Gottipati Ponnari , Oliver F Javier , Helleday Thomas , Hammond Ester M. , Bristow Robert G. 
Published: June 2012

Abstract
Acute and chronic hypoxia exists within the 3D microenvironment of solid tumors and drives therapy resistance, genetic instability and metastasis. Replicating cells exposed to either severe acute hypoxia (16 h with 0.02% O2) followed by reoxygenation or moderate chronic hypoxia (72 h with 0.2% O2) treatments had decreased RAD51 protein expression and homologous recombination (HR) function. As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of HR-defective hypoxic cells to PARP inhibition. Although PARP inhibition did not affect HR, we observed increased clonogenic killing in HR-deficient hypoxic cells following inhibition or siRNA depletion of PARP1. PARP1−/− MEFs showed a proliferative disadvantage and a lack of cell adaption to hypoxia when compared to PARP1+/+ MEFs. PARP-inhibited hypoxic cells accumulated H2AX and 53BP1 foci as a consequence of altered DNA replication firing leading to S phase-specific cell killing. In support of this proposed mode of action, PARP inhibitor treated RKO xenografts showed increased H2AX-positivity and cell death across hypoxic cell gradients in subregions with suppressed RAD51 expression.
We conclude that the repair defects observed in hypoxic cells can sensitize hypoxic cells to PARP inhibition as a consequence of microenvironment-mediated “contextual synthetic lethality”. As all solid tumors contain hypoxic cells, this may broaden the clinical utility of PARP inhibition in cancer therapy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A115.
Abstract A12: Variation in response to triple VEGFR inhibitor tivozanib in mouse models of hepatocellular carcinoma
Authors: Farlow Samuel , Potz Darren , Zi Tong , Sun Xiaojian , Lin Jie , Chiu Maria Isabel , Robinson Murray O. , Heyer Joerg , Zhou Yinghui 
Published: June 2012

Abstract
Liver cancer is the 5th most common cancer type and the 3rd leading cause of cancer related death worldwide. In the US, the number of new cases continues to rise and reached 19,000 per year in 2004, more than doubling the number twenty years ago. The limited treatment options include surgery, radiation therapy and chemotherapy. Unfortunately, the prognosis for most liver cancer patients is extremely poor due to late diagnosis, and the 5 year overall survival rate is less than 10%. Recent approval of sorafenib suggests that VEGFR inhibition might be beneficial to the survival of HCC patients. Hepatocellular carcinoma (HCC) originates from hepatocytes and accounts for 80–90% of the cases of liver cancer. Genetic alterations found in human HCCs include loss of major tumor suppressor genes (p53, Ink4a/Arf, PTEN, and NF1) as well as activation of oncogenic pathways through mutation and/or amplification (RAS/MapK, PI3K, and Wnt/beta-catenin pathways). We generated primary HCCs in mouse using a recently-developed tissue reconstitution approach. Briefly, we isolated hepatoblasts from p53 deficient donor embryos, infected the cells with retroviruses carrying the clinically relevant human oncogenes Myc or mutant Kras, and transplanted them back to the liver of recipient mice through intra-splenic injection. These mice developed tumors in the liver with a latency of 2–5 months and penetrance of 30–50%. Histological examination demonstrated that these tumors resemble the features of human HCCs.
Interestingly, a quantitative analysis of the vasculature in these tumors revealed a broad range of vessel size and vessel density, indicating that angiogenesis in these tumors are likely driven by different molecular mechanisms. We sought to explore the variation in angiogenic phenotypes by examining the response of various tumors with the ATP competitive small molecule VEGFR inhibitor tivozanib (AV-951). Tivozanib exhibits picomolar inhibitory activity against all three VEGF receptors, a multi-day T1/2 in humans, and demonstrates robust clinical activity demonstrated in renal cell carcinoma, the signal tumor type for VEGF pathway inhibition.
Consistent with the variation in angiogenic phenotypes, variation in response to tivozanib was observed: a subset of these tumors exhibited exquisite sensitivity to tivozanib, whereas other tumors were significantly less sensitive. These results are in line with the clinical benefit of Sorafenib on patients with hepatocellular carcinoma. These data, taken together, strongly suggest that anti-angiogenesis therapy can be a potential treatment option for a subset of HCC patients. Since our HCC models captured the response of human HCCs, they provide a valuable tool for identification of biomarkers for patient selection.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A12.
Abstract A121: Novel PARP inhibitors with potent antitumor activity as single-agent and combination therapies
Authors: Wang Bing , Chu Daniel , Feng Ying , Yu Xin , Myers Peter , Post Leonard , Shen Yuqiao (Jerry) 
Published: June 2012

Abstract
Poly (ADP-ribose) polymerases (PARP) -1 and -2 are key enzymes that are activated by DNA damage and play a critical role in the base excision DNA repair (BER) pathway. Previous studies have indicated that inhibitors of PARP-1 and -2 could enhance the efficacy of radiation therapy and chemotherapies by preventing cancer cells from repairing DNA damage. In addition, PARP inhibitors have been shown to selectively kill cancer cells that are deficient in BRCA-1 or BRCA-2 function. In this study, we describe the antitumor activity of a series of novel PARP inhibitors in single-agent therapy and in combination with standard chemotherapies. One of the compounds in this series, LT-00673, inhibits PARP-1 with IC50 at sub-nanomolar (nM) concentration. In cultured human cancer cells, LT-00673 significantly enhances the cytotoxic efficacy of both Temozolomide and SN-38 (active metabolite of Irinotecan). LT-00673 also demonstrates single-agent cytotoxicity in BRCA-1 mutant (MX-1, IC50 = 0.3 nM) and BRCA-2 mutant cells (Capan-1, IC50 = 5 nM). In contrast, in MRC-5 normal human fibroblast and other tumor cell lines with wild-type BRCA-1 and BRCA-2 genes, IC50 of LT-00673 ranges between 90 nM and 1.9 µM. In rat pharmacokinetic studies, LT-00673 displays &gt;50% oral bioavailability and pharmacokinetic properties that enable single daily dosing. In xenograft tumor model studies, daily oral dosing of LT-00673 significantly enhances the antitumor effects of cytotoxic therapies in a dose-dependent manner. In addition, once daily oral dosing of LT-00673 at 0.33 mg/kg/day results in complete response in the MX-1 tumor model. Pharmacodynamic studies have demonstrated potent PARP inhibition by LT-00673 in tumor biopsies. Off-target molecular screening did not identify significant non-specific activity for this class of PARP inhibitors. In summary, LT-00673 displays potent antitumor activity, along with oral bioavailability and pharmacokinetic properties that support in vivo efficacy on single daily doses, both as single-agent therapy and in combination with cytotoxic chemotherapies.
Conclusion: LT-00673 shows promising in vitro and in vivo activities and is currently in preclinical development.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A121.
Abstract A125: Profound impact of the nucleotide excision repair proteins XPC and CSB, but not ERCC1, on the resistance to an antitumor alkylator destabilizing local DNA duplex structure
Authors: Poindessous Virginie , Rocca Céline J. , Soares Daniele G. , El Ouadrani Karima , Sarasin Alain , Guérin Eric , Henriques João A. P. , de Gramont Aimery , Escargueil Alexandre E. , Larsen Annette K. 
Published: June 2012

Abstract
Backgound: Nucleotide excision repair (NER) is one of our most versatile DNA repair pathways. NER plays an important role in the repair of platinum adducts, and expression levels of the ERCC1 endonuclease, the last step in the NER process, is widely considered as a useful clinical marker for NER activity. S23906 is an antitumor alkaloid forming bulky monofunctional adducts with the capacity to destabilize local base pairing, which is a unique feature among anticancer agents. The purpose of the present study was to determine the influence of NER on the sensitivity to this unusual agent.
Experimental: A panel of primary and transformed cell lines derived from patients with xeroderma pigmentosum or Cokayne syndrome was used to determine the role of each step in the NER pathway on the response to S23906. KB carcinoma cells with acquired resistance to S23906 were used for further characterization.
Results: We here show that cells deficient for either global genome NER or transcription-coupled NER are profoundly sensitive to S23906, which for cells deficient in XPC, CSB and XPA far exceed the sensitivity observed for cisplatin and UV, two classical NER substrates. In contrast, cells deficient in ERCC1 and XPF, the last step in the NER pathway, showed modest sensitivity to S23906, compared to wt cells. Acquired resistance to S23906 was accompanied by cross-resistance to cisplatin and UV irradiation as well as by an important increase in NER activity as determined by unscheduled DNA synthesis and transcriptional recovery. Accordingly, resistant cells show up to 5-fold upregulation of XPC, CSB and XPA proteins. In contrast, no detectable alterations were observed for ERCC1.
Conclusions: These results show that upregulation of NER activity in cells with acquired resistance to S23906 is associated with upregulation of XPC and CSB, the two proteins needed for the initial steps of the NER pathway, but without detectable changes in ERCC1 expression, which is needed for the last step of the pathway. Our results suggest that ERCC1 is neither rate-limiting nor representative of NER activity, and is unlikely to be of value as a predictive marker for bulky monofunctional compounds. We further suggest that the value of ERCC1 as a predictive marker for platinum compounds and other cross-linking agents may be based on its functions in recombination repair, cross link repair and telomere maintenance, rather than its role in NER.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A125.
Abstract A146: The role of cystine transport in darinaparsin-induced cell death
Authors: Garnier Nicolas M. , Gu Yuxuan , Kourelis Maria , Mann Koren K. , Bohle David S. , Miller Wilson H. 
Published: June 2012

Abstract
Darinaparsin (ZIO-101; S-dimethylarsino-glutathione; Dar) is a promising novel organic arsenical, currently undergoing clinical studies in various malignancies. Dar is synthesized by conjugating dimethylarsenic (DMA) to glutathione (GSH) and shows enhanced activity as compared to arsenic trioxide (ATO). Dar induces more intracellular arsenic accumulation, oxidative stress (OS) and cell death than ATO. However, Dar has a maximum tolerated dose that is 35-fold higher than ATO. The mechanisms responsible for the lower toxicity and higher anti-tumor efficacy associated with Dar remains to be elucidated. Here, we propose a mechanism for Dar import that might, at least partially, explain the enhanced efficacy.
Preliminary results show that both ATO and Dar induce the expression of the cystine importer xCT and that high levels of xCT expression correlates with high sensitivity to Dar, as shown in a NCI60 panel. The cystine/cysteine redox cycle consists of cystine uptake, intracellular reduction to cysteine which is secreted into the extracellular space where it is oxidized back to cystine. Intracellular cysteine (Cys-SH) can be used for the synthesis of GSH, the major intracellular OS scavenger. We find that increased extracellular concentration of L-cysteine or equivalent thiols during Dar treatment inhibits intracellular arsenic accumulation, measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), as well as apoptosis, assessed by propidium iodide staining quantitated by flow cytometry. Thus, we hypothesized that L-cysteine or equivalent thiols might prevent Dar import.
GSH itself is not imported in the cell, so we thought it unlikely that darinaparsin would enter the cell without being somehow modified. Structural analysis of darinaparsin reveals putative break-down products: dimethylarsino-cysteine (DMAC), dimethylarsenic III (DMA III) and dimethylarsenic V (DMA V). ICP-MS experiments showed that treatment with DMA III and DMA V does not lead to significant intracellular accumulation of arsenic, and correlates with their inability to induce cell death. However, DMAC is very similar to Dar in terms of intracellular accumulation of arsenic, G2/M arrest and cell death. As with Dar, thiols were able to inhibit DMAC-induced cell death.
In summary, we hypothesize that darinaparsin gets transformed extracellularly into DMAC, which is imported via xCT or another cystine/cysteine importing system. Cells respond to arsenic-induced OS by increasing cystine uptake, which may selectively increase the anti-cancer activity of Dar. The fact that cancer cells, under a high OS state, have an increase need for GSH, i.e. for cystine, might explain the fewer systemic toxicities reported with Dar. Moreover, cystine/cysteine importers may be valuable biomarkers to predict Dar sensitivity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A146.
Abstract A158: Development of CYP26 inhibitors to optimize the treatment of neuroblastoma with retinoic acid
Authors: Bridgens Caroline E. , Veal Gareth J. , Redfern Christopher P. F. , Gomaa Mohamed S. , Brancale Andrea , Armstrong Jane L. , Simons Claire 
Published: June 2012

Abstract
Neuroblastoma is the most common extra-cranial malignant solid tumor of childhood. It is diagnosed in approximately 800 children per annum in the USA, and currently has a poor prognosis for high-risk patients.
Neuroblastoma treatment is limited by the development of resistance to retinoic acid (RA). Inhibition of CYP26, the enzyme primarily associated with RA-metabolism, has been demonstrated to enhance concentrations of RA both in vitro and in vivo. It is anticipated that these results may be translated into improved clinical therapy for neuroblastoma.
We have designed, prepared and performed extensive in vitro testing of a small library of novel CYP26 inhibitors. A microsomal CYP26 inhibition assay was used to screen all novel inhibitors to generate initial IC50 values. The most promising compounds were further investigated in cellular assays, employing SH-SY5Y neuroblastoma cells, including proliferation assays and measurement of CYP26A1 mRNA induction, a sensitive biomarker reflecting intracellular RA concentrations. CYP selectivity assays have also been performed, providing data to assist in the selection of lead compounds that will have a reduced probability of possessing off-target effects on other CYP enzymes, a fundamental limitation in previous attempts to target CYP26. A number of compounds have exhibited impressive CYP26 inhibitory potency, with IC50 values &lt;10 nM observed in microsomal assays. Co-incubation of SH-SY5Y cells with lead compounds and low levels of RA increased the level of expression of CYP26A1 mRNA up to 30-fold, relative to SH-SY5Y cells treated with RA alone. This potentiation reflects the ability of these novel inhibitors to enhance and prolong the in vitro effects of RA. Our research program has generated a number of highly potent CYP26 inhibitors to be tested in vivo. It is anticipated that these studies will lead to the generation of compounds which may be used in combination with RA to improve the future treatment of neuroblastoma.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A158.