bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3839: Is recent decline in breast cancer incidence equal across different US racial groups?
Authors: Huo Dezheng , Olopade Olufunmilayo I 
Published: May 2019

Abstract
Background: Recently, a sharp decline in breast cancer incidence rate was observed between 2002 and 2003 in the United States, evident only in women aged 50 years or older and for estrogen-receptor positive breast cancer. The plausible explanations for the decline have been controversial. Moreover, it is unclear if the reduction in incidence is equally distributed across all racial groups or whether the trends in breast cancers of different stages are similar.
Methods: We examined temporal trends between 2000 and 2004 in invasive and in situ female breast cancer by race and tumor stage, using data from 17 cancer registries of the Surveillance, Epidemiology, and End Results program. Incidence rates were age-adjusted to the 2000 US standard population. We used jointpoint regressions to fit a series of joined straight lines on a log scale to the trends of quarterly, age-adjusted rates in women aged 50 to 69 years.
Results: In Caucasian women, the incidence rate of invasive breast cancer was stable from 2000 to mid-2002 (-0.15% per quarter), significantly decreased to the end of 2003 (-2.41% per quarter, p=0.004), and stable to the end of 2004 (0.63% per quarter). Similar trends were seen for the rates of localized tumors and regional and distant tumors in Caucasians. The incidence rate of invasive breast cancer did not change significantly in the other racial groups: the quarterly changes throughout the study period were 0.07% in African Americans, -0.14% in American Indian/Alaska Natives, and -0.46% in Asian American/Pacific Islanders. The incidence rate of in situ breast cancer was stable in Caucasians (-0.23% per quarter), African Americans (0.26% per quarter), and American Indian/Alaska Natives (-0.97% per quarter). In Asian American/Pacific Islanders, the rate of in situ breast cancer was marginally significantly increased from 2000 to the mid-2002 (2.09% per quarter, p=0.054) but decreased to the end of 2004 (-3.20% per quarter, p=0.01).
Conclusions: The decline in breast cancer incidence was not equal across US racial groups and the benefit was confined to Caucasians. This racial disparity is consistent with the hypothesis that discontinuation of hormone replacement therapy (HRT) may have caused the dramatic reduction. Compared with Caucasians, African Americans are more likely to have estrogen receptor negative tumors and less likely to use HRT, and thereby less likely to show a benefit from discontinuation of HRT. The finding that the rate of invasive breast cancer (but not in situ cancer) decreased suggests that exogenous estrogen serves as a promoter rather than an initiator of breast cancer. The trend of in situ cancer in Asian American/Pacific Islanders may be a result of slower uptake of mammographic screening in this population.
Abstract 4908: Antennapedia "trojan" peptide delivers p21 protein resulting in tumor eradication
Authors: Kousparou Christina , Deonarain Mahendra , Stylianou Spyros , Epenetos Agamemnon 
Published: May 2019

Abstract
The purpose of this study is to utilize the “trojan horse” approach to deliver an effector function to cancer cells in vitro and in vivo.
Many cell-translocating trojan peptides have been studied in the context of therapeutic protein delivery, including the homeodomain region of the Drosophila Antennapedia protein. The mechanism of transduction of this peptide relies on the presence of basic aminoacids arranged in helical conformations, which are important for lipid interactions and for penetration of the membrane.
The tumor-suppressor protein p21 is important in many key cell division processes including G1 arrest leading to apoptosis of damaged cells. Restoring p21 protein to tumor cells lacking functional p21 could lead to tumor cells regaining higher chemosensitivity and the ability to die upon genotoxic insult.
Our experiments investigate the tumor inhibitory and therapeutic potential of a fusion protein comprising of the ‘trojan’ peptide Antennapedia and p21. The effects of administration of Antennapedia-p21 on the growth of cultured cancer cells and on tumors implanted into nude mice were evaluated. In vitro studies showed that nuclear localization of p21 protein could be achieved using the Antennapedia carrier. The efficacy of this treatment on cells was also determined in combination with conventional chemotherapy. Treatment with Antp-p21 induced cell-cycle arrest leading to the inhibition of tumor cell growth.
Intra-venous administration of the fusion protein to tumor-bearing mice inhibited tumor growth and prolonged overall survival. Furthermore, co-administration of the fusion protein with conventional chemotherapeutic agents resulted in enhanced growth inhibitory effects, tumor eradication in 40% of animals and significant reduction in tumor burden in 100% of animals.
In conclusion, our findings show that we can utilize the “trojan horse” approach to deliver an effector function to cancer cells in vitro and in vivo and achieve tumor eradication. The efficacy of our anti-tumor growth modality in combination with conventionally used anti-neoplastic medication suggests that it can be considered as a promising therapeutic drug for the management of a wide range of carcinomas.
Abstract 5000: The functional stem cell marker aldehyde dehydrogenase enhances pancreatic cancer stem cell isolation and correlates with clinical prognosis
Authors: Rasheed Zeshaan A , Yang Jie , Wang Qiuju , Freed Irwin , Koorstra Jan-Bart , Hong Seung-Mo , He Xiaobing , Berman David , Laheru Daniel , Hidalgo Manuel , Jimeno Antonio , Maitra Anirban , Matsui William H 
Published: May 2019

Abstract
Pancreatic adenocarcinoma is a highly aggressive cancer that is largely resistant to current therapies and portends a median survival for patients of 9-12 months. Resistance may be due to a subpopulation of cells that are chemoresistant and able to support tumor propagation, such as cancer stem cells (CSCs). CSCs have emerged as attractive therapeutic targets, but the development of effective therapies requires the isolation of highly purified cell populations. Surface antigen expression has been used to identify CSC in most systems, however, methods based on functional properties, such as Hoechst dye exclusion or aldehyde dehydrogenase (ALDH) activity, can enhance stem cell isolation from normal and malignant tissues. We compared CSCs from pancreatic adenocarcinomas isolated by cell surface phenotype, ALDH activity, or both. Initially, we studied ALDH expression in human pancreatic cancer cell lines (CAPAN-1, DAN-G, CFPAC-1) using the Aldefluor assay. We found that each line contained a small population of ALDH+ cells (0.9-6.5% of total cells) that demonstrated increased clonogenic growth potential both in vitro and in vivo compared to ALDH- cells. Next, we compared ALDH expression with the published pancreatic CSC phenotype (CD24+CD44+) in cell lines and low-passage xenografts derived from primary human tumor specimens. Interestingly, we found that the putative CSC populations were only partially overlapping since 7-18.2% of the ALDH+ cells were CD44+CD24+ and only 4.2-36.2% of the CD44+CD24+ cells expressed ALDH. We compared CD44+CD24+ and CD44+CD24+ALDH+ cells isolated from 5 unique human pancreatic cancer xenografts and found that the CD44+CD24+ALDH+ cells were more tumorgenic in NOD/SCID mice. We also evaluated ALDH expression in primary pathologic specimen from 268 patients with pancreatic cancer by immunohistochemistry and found small, intensely positive cells with round or oval nuclei near the base of cancerous glands or at the invasive front in 90 (34%) of those patients. Furthermore, the presence of these cells was significantly associated with poorer overall survival (14 vs. 18 mos, p=0.02). We have begun to evaluate the mechanism by which pancreatic CSCs may be involved in more aggressive disease and found that CD44+CD24+ALDH+ cells isolated from tumor xenografts have significantly lower expression of E-cadherin and higher expression of Slug, a transcriptional repressor of E-cadherin, compared to ALDH+ or ALDH- cells. Therefore, ALDH appears to mark highly clonogenic pancreatic CSCs. Moreover, increased features associated with epithelial-to-mesenchymal transition may play a role in the correlation of ALDH+ cells with long-term outcomes.
Abstract 557: Aging and DNA methylation in Alu and LINE-1 repeated elements
Authors: Cantone Laura , Bollati Valentina , Wright Robert , Litonjua Augusto , Tarantini Letizia , Suh Helen , Sparrow David , Vokonas Pantel , Baccarelli Andrea , Schwartz Joel 
Published: May 2019

Abstract
DNA methylation exhibits a gradual genome-wide decrease in association with aging and the rate of decrease appears to be inversely proportional to life expectancy. The observed age-related increase in cancer incidence cannot be explained entirely by genetic mutation rates. Accumulation of epigenetic alterations during aging may contribute to determine the malignant transformation. In particular, global DNA hypomethylation, which has been associated with repetitive DNA demethylation may promote chromosomal instability. About 55% of the human genome consists of repetitive elements, which are for the most part made up of approximately 500,000 long interspersed nucleotide elements (LINE elements) and 1.4 million Alu repetitive elements, which are normally heavily methylated. DNA methylation of LINE-1 and Alu elements has shown to correlate with total 5mC content and thus used to estimate global DNA methylation. In humans, LINEs are the major source of insertional mutagenesis, being involved in both germinal and somatic mutant phenotypes. Alu retrotransposition has also been associated with human disease. However, whether LINE/Alu methylation decreases with age has never been established.
We examined the epigenetic effect of aging on DNA methylation in repetitive elements Alu and LINE-1, measured in peripheral blood DNA from 693 subjects evaluated between 1999-2006 as part of the Normative Aging Study (NAS), a longitudinal study established in 1963 by the U.S. Veterans Administration. We measured DNA methylation through quantitative analysis by PCR-Pyrosequencing. Two different blood samples, taken approximately three years apart, were available for each subject.
Repeated element methylation was negatively associated with age. In linear regression, we found a decrease equal to 0.016% for LINE-1 (p=0.07) and 0.015% for Alu (p=0.007), for each year increase. We did not find significant changes between repeated measures taken three years apart from each other on the same subjects. The two repeated measures showed high correlation for both Alu (n=300, r=0.46, p&lt;0.001) for Alu and LINE-1 (n=303, r=0.59, p&lt;0.001).
DNA methylation of LINE-1 and Alu repetitive elements is inversely correlated with age, although is not captured in repeated measurements taken over a three years period. Such age-related decrease in methylation may increase the risk of mutational events potentially leading to cancer development.
Abstract 5814: Association between ADH1B and ADH1C haplotype tag SNPs and breast cancer risk, and the interaction with alcohol drinking
Authors: Marian Catalin , Sucheston Lara , Nie Jing , Millen Amy , Goerlitz David , Trevisan Maurizio , Russell M , Nochajski T , Ambrosone CB , Hutson A , Edge SB , Vito D , Shields Peter G , Freudenheim Jo L 
Published: May 2019

Abstract
Alcohol consumption has been found to be associated with breast cancer with some consistency. Alcohol dehydrogenase is rate limiting in alcohol metabolism. We investigated the association of haplotype tag SNPs in ADH1B and ADH1C with breast cancer risk and the interaction with alcohol drinking in a population-based case control study (the WEB Study) conducted in western New York between 1996 and 2001. Genomic DNA and SNP genotyping was performed by allelic discrimination real time PCR for 991 cases and 1698 controls. Haplotype tag SNPs were selected from the Caucasian HapMap data. Lifetime alcohol consumption was queried by interview. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Backwards selection was employed to obtain the most parsimonious model starting with the full model with interactions. Two tag SNPs, rs1042026 in ADH1B and rs1614972 in ADH1C, were associated with risk for postmenopausal women. The ADH1B SNP rs1042026 located in the 3’UTR is in LD with several functional SNPs from ADH6, ADH1A, ADH1B and ADH1C. This SNP was in Hardy Weinberg equilibrium in the postmenopausal control and not in postmenopausal cases, which strengthens the evidence of association. This SNP showed evidence of significant interaction with alcohol consumption. The OR for postmenopausal breast cancer in women with both CC genotype and who consume alcohol versus without the AA genotype and who abstain was 1.94, 95%CI 1.13-3.30. In addition, we found evidence of a trend for dose response depending on the amount of alcohol consumption when alcohol consumption was examined in three categories of abstainers, low and high consumption (p=0.08). The ADH1C SNP rs1614972 located in intron 8 is in LD with other six nonsynonymous exonic SNPs including the functional I350V (rs698). There was an interaction with alcohol consumption with the presence of the CC genotype and risk conferring a protective effect varying inversely proportional with the drinking level (p=0.0092). Moreover, the CC genotype decreased the odds of breast cancer in women who consume alcohol versus those that abstain regardless of the menopausal status (OR=0.56, 95%CI 0.35-0.90). In conclusion, haplotype tag SNPs in ADH1B and ADH1C were associated with breast cancer risk especially in postmenopausal women, and showed evidence of significant interaction with alcohol consumption.
Supported by the following grants: DAMD-17-03-1-0446, DAMD-17-00-1-0417 and NCI-RO1CA92040
Marian C. was supported by an AVON-AACR International Scholar in Breast Cancer Research award
Abstract LB-202: Phase 1 dose escalation trial of the novel vascular disrupting agent NPI-2358
Authors: Mita Monica , Spear Matthew A , Yee Lorrin K , Papadopoulos K P , Heath Elisabeth , Romero Ofelia , Lloyd G Kenneth , Cropp Gillian , Mita Alain , LoRusso Patricia 
Published: May 2019

Abstract
Background: NPI-2358 is a novel vascular disrupting agent that inhibits tubulin polymerization leading to tumor vascular endothelial destabilization. NPI-2358 selectively induces tumor vascular collapse resulting in tumor regression and potentiates other oncology agents in preclinical tumor models. Preclinical data suggest NPI-2358 may have advantages in terms of safety profile and activity.
Methods: In this study the dose of NPI-2358 was escalated from 2 to 30 mg/m2 in patients with advanced solid tumors and lymphomas. Patients were treated with a weekly IV infusion of NPI-2358 for 3 weeks in 4-week cycles. The study utilized a dynamic accelerated dose titration (DADT) design in which the dose of NPI-2358 was escalated in cohorts, in which any cohort could consist of 1 patient provided no ≥Grade 2 adverse event is reported in the prior cohort, otherwise the cohort consisted of at least 3 patients. In addition to weekly safety monitoring, ECG, ECHO, and PK were obtained on day 1 and day 15. DCE-MRI were performed at baseline, day 2 then every other cycle and end of study as feasible, to assess changes in tumor blood flow and vascular permeability as reflected in the volume transfer constant (Ktrans). An improved two-compartment model is utilized which incorporates motion correction and an automated arterial input function. This is expected to improve the accuracy and reproducibility in the estimation of Ktrans by eliminating variability associated with subject motion, contrast injection, and cardiac output.
Results: Twenty-five subjects were enrolled in the dose escalation phase. We selected 30 mg/m2 as the RP2D, based on adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient elevations in blood pressure. DCE-MRI demonstrated decreases in Ktrans beginning at 13.5 mg/m2, and a 16-82% decrease in patients evaluated at 30 mg/m2. Decreasing Ktrans over multiple treatment cycles was seen in the two patients that underwent repeat DCE-MRI imaging. Five patients had stable disease for two or more cycles: pancreatic adenocarcinoma (4 cycles), colorectal carcinoma (2 cycles), anal squamous cell carcinoma (3 cycles), adrenalcortical carcinoma (2 cycles), and melanoma (2 cycles). Average Cmax and AUCtotal have increased from 34 to 610 ng/ml, and from 101 to 3998 ng/ml/hr respectively. No drug accumulation was observed. For all patients T1/2 was 5.8 ±3.2 h, CL was 34.1 ±26 L/h, and Vss was 211±61 L.Conclusions: At the RP2D NPI-2358 produced tolerable toxicities, while eliciting decreases in tumor blood flow by DCE-MRI. Maximum effect on Ktrans appeared to increase with increasing dose and time on treatment. Cmax and AUC increased with dose, without drug accumulation. NPI-2358 is currently proceeding into Phase Ib/II trials in solid tumor malignancies.
Abstract LB-239: An rnai sensitization screen identifies compensatory IKKα activation during IKKβ inhibition
Authors: Lam Lloyd T , Davis R. Eric , Ngo Vu , Wright George , Lenz Georg , Zhao Hong , Yu Xin , Dang Lenny , Staudt Louis M 
Published: May 2019

Abstract
Introduction: We previously described a subtype of diffuse large B-cell lymphoma (DLBCL) termed activated B-cell-like (ABC) DLBCL that depends on NF-κB activity for survival, and showed that a specific small molecule inhibitor of the upstream kinase IKKβ is selectively toxic to this subgroup of lymphoma.
Methods: To identify proteins or pathways whose inhibition may synergize with the toxicity of IKKβ inhibition in ABC DLBCL, we performed an “RNAi sensitization” screen with an RNA interference library, directed against 500 protein kinases, in the presence of the specific IKKβ inhibitor in an ABC DLBCL cell line.
Results: Short hairpin RNA (shRNAs) targeting IKKα, a component of the IKK complex, enhanced killing by the IKKβ inhibitor in ABC DLBCL cell lines but not other lymphoma cell lines. Gene expression profiling and NF-κB-specific reporter assays showed that IKKα shRNA affects the classical NF-κB pathway, further inhibiting the phosphorylation of IκBα only in the presence of the specific IKKβ inhibitor. Further studies in physiologic models of lymphocyte stimulation showed that compensatory IKKα activity occurs in other settings.
Conclusions: These results demonstrate that loss-of-function screens in the presence of a defined inhibitor can identify therapeutic targets in cancers, providing a rationale for combination therapies targeting multiple pathways critical to an individual cancer.
Abstract P1-03-06: Improvement in risk predictive value of Nottingham prognostic index by determining GP88 tumor tissue expression for estrogen receptor positive breast cancer patients
Authors: Serrero G , Hawkins DM , Bejarano PA , Ioffe O , Tkaczuk KR , Elliott RE , Head JF , Phillips J , Godwin AK , Weaver J , Hicks D , Yue B 
Published: May 2019

Abstract
Background: The Nottingham Prognostic Index (NPI), which includes nodal status, tumor size and histological grade was established to provide predictive value information on post-surgery survival for primary breast cancer patients. Attempts to improve NPI's performance have included addition of other biomarker expression and morphological features such as vascular invasion. In the present study, we investigated whether expression of the autocrine growth and survival factor GP88 (progranulin), known to be overexpressed in breast cancer, whereas it is negative in normal mammary tissue, would improve NPI's predictive value.
Methods: We examined the tumor tissue GP88 expression by immunohistochemistry (IHC) in formalin fixed paraffin embedded tissue sections from 508 cases of estrogen receptor positive (ER+) invasive ductal carcinoma (IDC) with known clinical outcomes (disease-free and overall survivals) and with known NPI. GP88 IHC tumor tissue expression was determined using an anti-GP88 antibody (clone 6B3) developed in our laboratory. GP88 expression was scored (0, 1+, 2+, 3+) by two board certified pathologists and classified into two IHC score groups of GP88 &lt; 3+ (0, 1+, 2+) and GP88 = 3+. The correlation between GP88 scoring, NPI and disease-free (DFS) and overall survival (OS) outcomes was then examined by Kaplan Meier analysis, Cox proportional Hazard (CPH) ratio and Pearson's C2 test.
Results: Kaplan-Meier survival graphs categorized by NPI scores (&lt; 3.4, 3.4-5.4, and &gt;5.4) and by GP88 expression (&lt; 3+ and 3+) showed that for each NPI subgroup, patients with GP88 IHC score of 3+ had a worse disease-free survival (DFS) and overall survival (OS) than patients within the same NPI subgroup with tumors that had GP88 IHC score &lt; 3+. When adjusted for NPI, high GP88 score was highly significantly associated with recurrence with a hazard ratio of 3.30 (95% CI 2.12 to 5.14).
Conclusions: The data suggest that measuring GP88 tumor tissue expression by IHC at time of diagnosis for breast cancer patients with primary ER+ IDC could provide recurrence prediction and survival information complementary to that provided by the determination of NPI alone and thus may be useful for risk management of patients diagnosed with breast cancer.
Citation Format: Serrero G, Hawkins DM, Bejarano PA, Ioffe O, Tkaczuk KR, Elliott RE, Head JF, Phillips J, Godwin AK, Weaver J, Hicks D, Yue B. Improvement in risk predictive value of Nottingham prognostic index by determining GP88 tumor tissue expression for estrogen receptor positive breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-06.