bluuebunny/crossref_metadata_2025 huggingface dataset:
MOCVD ZnO/Screen Printed Ag Back Reflector for Flexible Thin Film Silicon Solar Cell Application
Authors: Limmanee Amornrat , Krudtad Patipan , Songtrai Sasiwimon , Jaroensathainchok Suttinan , Krajangsang Taweewat , Sritharathikhun Jaran , Sriprapha Kobsak
Published: January 2014

We have prepared Ag back electrode by screen printing technique and developed MOCVD ZnO/screen printed Ag back reflector for flexible thin film silicon solar cell application. A discontinuity and poor contact interface between the MOCVD ZnO and screen printed Ag layers caused poor open circuit voltage (Voc) and low fill factor (FF); however, an insertion of a thin sputtered ZnO layer at the interface could solve this problem. The n type hydrogenated amorphous silicon (a-Si:H) film is preferable for the deposition on the surface of MOCVD ZnO film rather than the microcrystalline film due to its less sensitivity to textured surface, and this allowed an improvement in the FF. The n-i-p flexible amorphous silicon solar cell using the MOCVD ZnO/screen printed Ag back reflector showed an initial efficiency of 6.2% withVoc=0.86 V,Jsc=12.4 mA/cm2, and FF = 0.58 (1 cm2). The identical quantum efficiency and comparable performance to the cells using conventional sputtered Ag back electrode have verified the potential of the MOCVD ZnO/screen printed Ag back reflector and possible opportunity to use the screen printed Ag thick film for flexible thin film silicon solar cells.
Antioxidant Effects of Bovine Lactoferrin on Dexamethasone-Induced Hypertension in Rat
Authors: Safaeian Leila , Zabolian Hadi
Published: January 2014

Dexamethasone- (Dex-) induced hypertension is associated with enhanced oxidative stress. Lactoferrin (LF) is an iron-binding glycoprotein with antihypertensive properties. In this study, we investigated the effect of chronic administration of LF on oxidative stress and hypertension upon Dex administration. Male Wistar rats were treated by Dex (30 μg/kg/day subcutaneously) or saline for 14 days. Oral bovine LF (30, 100, 300 mg/kg) was given from day 8 to 14 in a reversal study. In a prevention study, rats received 4 days of LF treatment followed by Dex and continued during the test period. Systolic blood pressure (SBP) was measured using tail-cuff method. Thymus weight was used as a marker of glucocorticoid activity. Plasma hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) value were determined. Dexamethasone significantly increased SBP and plasma H2O2 level and decreased thymus and body weights. LF lowered (P<0.01) and dose dependently prevented (P<0.001) Dex-induced hypertension. LF prevented body weight loss and significantly reduced the elevated plasma H2O2 and increased FRAP values. Chronic administration of LF strongly reduced the blood pressure and production of ROS and improved antioxidant capacity in Dex-induced hypertension, suggesting the role of inhibition of oxidative stress as another mechanism of antihypertensive action of LF.
The Comparison of Pain Caused by Suprapubic Aspiration and Transurethral Catheterization Methods for Sterile Urine Collection in Neonates: A Randomized Controlled Study
Authors: Ghaffari Vajihe , Fattahi Saeed , Taheri Mohsen , Khademloo Mohammad , Farhadi Roya , Nakhshab Maryam
Published: January 2014

This study was performed to compare the levels of pain experienced by young infants undergoing either suprapubic aspiration (SPA) or transurethral catheterization (TUC) for the collection of sterile urine samples. This prospective randomized clinical trial was conducted in hospitalized neonates in a university-affiliated hospital. Patients who required urine cultures were randomly assigned into one of two groups, the SPA or TUC group. The infants’ faces were videotaped, and the changes in the facial expression and physiological parameters during the procedure were scored using the Premature Infant Pain Profile (PIPP) in a blind manner. The primary outcome was the severity of the pain experienced during each procedure, and the secondary outcomes were the success rate, the duration, and the complications of each procedure. Ninety-four percent of male infants in the TUC group and 77.3% in the SPA group were uncircumcised (P=0.1). The mean (SD) of the PIPP pain scores did not differ between groups (9.95 ± 3.7 in SPA and 9.64 ± 3.2 in TUC,P=0.6). The duration of TUC was longer. Both methods can be used to collect urine from neonates, but the difficulty of performing TUC on females and uncircumcised males should be considered.
Immunomodulation in Human Dendritic Cells Leads to Induction of Interferon-Gamma Production byLeishmania donovaniDerived KMP-11 Antigen via Activation of NF-κB in Indian Kala-Azar Patients
Authors: Chaudhary Rajesh , Amit Ajay , Yadav Anupam , Singh Anurag , Kumar Vikash , Singh S. K. , Narayan Shyam , Rabidas Vidyanand , Pandey K. , Kumar Anil , Das Pradeep , Bimal Sanjiva
Published: January 2014

Dendritic cells (DCs) and macrophages (MΦs) are well-known antigen presenting cells with an ability to produce IL-12 which indicates that they have potential of directing acquired immunity toward a Th1-biased response. The aim of this study was to examine the effect ofLeishmaniaspecific KMP-11 antigen through comparison of immune responses after presentation by DCs and MΦs to T cells in Indian patients with VL. Patients with DCS and MΦs were directed against a purifiedLeishmania donovaniantigen (KMP-11) and phytohaemagglutinin (PHA). The cytokines (IL-12, IL-10, and TGF-β) producing abilities of the DCs and MΦs against these antigens were determined by flow cytometry. The transcription factor (NF-κB) and T-cell cytokine support (IFN-γ, IL-10), which could be significant in effector immune function, were also determined. Severe hindrance in the immune protection due toLeishmaniaparasites, as revealed by decreased expression of IL-12 and upregulation of IL-10 and TGF-βexpression in the MΦs compared to DCs, occurred in VL patients. The production of IL-12 in response toL. donovaniKMP-11 antigen was increased in DCs which was reduced in MΦs of VL patients. In contrast, the presentation of KMP-11 antigen by DCs to T-lymphocytes in VL patients significantly increased the IFN-γproduced by these immune cells, whereas the levels of IL-10 were significantly elevated after presentation of KMP-11antigen by MΦs. The VL patients were observed with severely dysfunctional MΦs in terms of NF-κB activity that could be recovered only after stimulation of DCs withL. donovaniKMP-11 antigen. Immunologically the better competitiveness of KMP-11 antigen through a dendritic cell delivery system may be used to revert T-cell anergy, and control strategy can be designed accordingly against kala-azar.
Design of an Optimal Preview Controller for Linear Discrete-Time Descriptor Noncausal Multirate Systems
Authors: Cao Mengjuan , Liao Fucheng
Published: January 2014

The linear discrete-time descriptor noncausal multirate system is considered for the presentation of a new design approach for optimal preview control. First, according to the characteristics of causal controllability and causal observability, the descriptor noncausal system is constructed into a descriptor causal closed-loop system. Second, by using the characteristics of the causal system and elementary transformation, the descriptor causal closed-loop system is transformed into a normal system. Then, taking advantage of the discrete lifting technique, the normal multirate system is converted to a single-rate system. By making use of the standard preview control method, we construct the descriptor augmented error system. The quadratic performance index for the multirate system is given, which can be changed into one for the single-rate system. In addition, a new single-rate system is obtained, the optimal control law of which is given. Returning to the original system, the optimal preview controller for linear discrete-time descriptor noncausal multirate systems is derived. The stabilizability and detectability of the lifted single-rate system are discussed in detail. The optimal preview control design techniques are illustrated by simulation results for a simple example.
Estrogen-Responsive Genes Overlap with Triiodothyronine-Responsive Genes in a Breast Carcinoma Cell Line
Authors: Figueiredo Nancy Bueno , Cestari Sílvia Helena , Conde Sandro José , Luvizotto Renata Azevedo Melo , De Sibio Maria Teresa , Perone Denise , Katayama Maria Lúcia Hirata , Carraro Dirce Maria , Brentani Helena Paula , Brentani Maria Mitzi , Nogueira Célia Regina
Published: January 2014

It has been well established that estrogen plays an important role in the progression and treatment of breast cancer. However, the role of triiodothyronine (T3) remains controversial. We have previously shown its capacity to stimulate the development of positive estrogen receptor breast carcinoma, induce the expression of genes (PR, TGF-alpha) normally stimulated by estradiol (E2), and suppress genes (TGF-beta) normally inhibited by E2. Since T3regulates growth hormones, metabolism, and differentiation, it is important to verify its action on other genes normally induced by E2. Therefore, we used DNA microarrays to compare gene expression patterns in MCF-7 breast adenocarcinoma cells treated with E2and T3. Several genes were modulated by both E2and T3in MCF-7 cells (Student’st-test,P<0.05). Specifically, we found eight genes that were differentially expressed after treatment with both E2and T3, includingamphiregulin, fibulin 1, claudin 6, pericentriolar material 1, premature ovarian failure 1B, factor for adipocyte differentiation-104, sterile alpha motif domain containing 9, and likely ortholog of rat vacuole membrane protein 1(fold change > 2.0, pFDR < 0.05). We confirmed our microarray results by real-time PCR. Our findings reveal that certain genes in MCF-7 cells can be regulated by both E2and T3.
Prior Autoimmune Disease and Risk of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma: A Systematic Review
Authors: McShane Charlene M. , Murray Liam J. , Landgren Ola , O'Rorke Michael A. , Korde Neha , Kunzmann Andrew T. , Ismail Mohammad Roshidi , Anderson Lesley A.
Published: January 2014

Background: Several observational studies have investigated autoimmune disease and subsequent risk of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. Findings have been largely inconsistent and hindered by the rarity and heterogeneity of the autoimmune disorders investigated. A systematic review of the literature was undertaken to evaluate the strength of the evidence linking prior autoimmune disease and risk of MGUS/multiple myeloma.

Methods: A broad search strategy using key terms for MGUS, multiple myeloma, and 50 autoimmune diseases was used to search four electronic databases (PubMed, Medline, Embase, and Web of Science) from inception through November 2011.

Results: A total of 52 studies met the inclusion criteria, of which 32 were suitably comparable to perform a meta-analysis. “Any autoimmune disorder” was associated with an increased risk of both MGUS [n = 760 patients; pooled relative risk (RR) 1.42; 95% confidence interval (CI), 1.14–1.75] and multiple myeloma (n>2,530 patients; RR 1.13, 95% CI, 1.04–1.22). This risk was disease dependent with only pernicious anemia showing an increased risk of both MGUS (RR 1.67; 95% CI, 1.21–2.31) and multiple myeloma (RR 1.50; 95% CI, 1.25–1.80).

Conclusions: Our findings, based on the largest number of autoimmune disorders and patients with MGUS/multiple myeloma reported to date, suggest that autoimmune diseases and/or their treatment may be important in the etiology of MGUS/multiple myeloma. The strong associations observed for pernicious anemia suggest that anemia seen in plasma cell dyscrasias may be of autoimmune origin.

Impact: Underlying mechanisms of autoimmune diseases, general immune dysfunction, and/or treatment of autoimmune diseases may be important in the pathogenesis of MGUS/multiple myeloma. Cancer Epidemiol Biomarkers Prev; 23(2); 332–42. ©2014 AACR.
Improved Recurrence-Free Survival with ARCON for Anemic Patients with Laryngeal Cancer
Authors: Janssens Geert O. , Rademakers Saskia E. , Terhaard Chris H. , Doornaert Patricia A. , Bijl Hendrik P. , van den Ende Piet , Chin Alim , Takes Robert P. , de Bree Remco , Hoogsteen Ilse J. , Bussink Johan , Span Paul N. , Kaanders Johannes H.
Published: January 2014

Purpose: Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial.

Experimental Design: Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient.

Results: Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed.

Conclusion: Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732). Clin Cancer Res; 20(5); 1345–54. ©2014 AACR.
FOXM1c Promotes Pancreatic Cancer Epithelial-to-Mesenchymal Transition and Metastasis via Upregulation of Expression of the Urokinase Plasminogen Activator System
Authors: Huang Chen , Xie Dacheng , Cui Jiujie , Li Qi , Gao Yong , Xie Keping
Published: January 2014

Purpose: The transcription factor Forkhead box M1 (FOXM1) plays important roles in the formation of several human tumors, including pancreatic cancer. However, the molecular mechanisms by which FOXM1 promotes pancreatic tumor epithelial-to-mesenchymal transition (EMT) and metastasis are unknown.

Experimental Design: The effect of altered expression of FOXM1 and urokinase-type plasminogen activator receptor (uPAR) on EMT and metastasis was examined using animal models of pancreatic cancer. Also, the underlying mechanisms of altered pancreatic cancer invasion and metastasis were analyzed using in vitro molecular biology assays. Finally, the clinical relevance of dysregulated FOXM1/uPAR signaling was investigated using pancreatic tumor and normal pancreatic tissue specimens.

Results: Pancreatic tumor specimens and cell lines predominantly overexpressed the FOXM1 isoform FOXM1c. FOXM1c overexpression promoted EMT in and migration, invasion, and metastasis of pancreatic cancer cells, whereas downregulation of FOXM1 expression inhibited these processes. The level of FOXM1 expression correlated directly with that of uPAR expression in pancreatic cancer cell lines and tumor specimens. Moreover, FOXM1c overexpression upregulated uPAR expression in pancreatic cancer cells, whereas inhibition of FOXM1 expression suppressed uPAR expression. Furthermore, transfection of FOXM1c into pancreatic cancer cells directly activated the uPAR promoter, whereas inhibition of FOXM1 expression by FOXM1 siRNA suppressed its activation in these cells. Finally, we identified an FOXM1-binding site in the uPAR promoter and demonstrated that FOXM1 protein bound directly to it. Deletion mutation of this site significantly attenuated uPAR promoter activity.

Conclusions: Our findings demonstrated that FOXM1c contributes to pancreatic cancer development and progression by enhancing uPAR gene transcription, and thus, tumor EMT and metastasis. Clin Cancer Res; 20(6); 1477–88. ©2014 AACR.
Insidious Changes in Stromal Matrix Fuel Cancer Progression
Authors: Miles Fayth L. , Sikes Robert A.
Published: January 2014

Reciprocal interactions between tumor and stromal cells propel cancer progression and metastasis. A complete understanding of the complex contributions of the tumor stroma to cancer progression necessitates a careful examination of the extracellular matrix (ECM), which is largely synthesized and modulated by cancer-associated fibroblasts. This structurally supportive meshwork serves as a signaling scaffold for a myriad of biologic processes and responses favoring tumor progression. The ECM is a repository for growth factors and cytokines that promote tumor growth, proliferation, and metastasis through diverse interactions with soluble and insoluble ECM components. Growth factors activated by proteases are involved in the initiation of cell signaling pathways essential to invasion and survival. Various transmembrane proteins produced by the cancer stroma bind the collagen and fibronectin-rich matrix to induce proliferation, adhesion, and migration of cancer cells, as well as protease activation. Integrins are critical liaisons between tumor cells and the surrounding stroma, and with their mechano-sensing ability, induce cell signaling pathways associated with contractility and migration. Proteoglycans also bind and interact with various matrix proteins in the tumor microenvironment to promote cancer progression. Together, these components function to mediate cross-talk between tumor cells and fibroblasts ultimately to promote tumor survival and metastasis. These stromal factors, which may be expressed differentially according to cancer stage, have prognostic utility and potential. This review examines changes in the ECM of cancer-associated fibroblasts induced through carcinogenesis, and the impact of these changes on cancer progression. The implication is that cancer progression, even in epithelial cancers, may be based in large part on changes in signaling from cancer-associated stromal cells. These changes may provide early prognostic indicators to further stratify patients during treatment or alter the timing of their follow-up visits and observations.

Visual Overview: http://mcr.aacrjournals.org/content/12/3/297/F1.large.jpg.

Mol Cancer Res; 12(3); 297–312. ©2014 AACR.
Abstract A106: Optimal strategies for selecting samples for sequencing families with a common cancer: The Genetic Epidemiology of Lung Cancer Consortium.
Authors: Amos Christopher , Bailey-Wilson Joan , Pinney Susan , Andrada Maria de , Gaba Colette , Mandal Diptasri , You Ming , Spitz Margaret , Anderson Marshall
Published: January 2014

In order to select samples that are optimally informative for sequence analysis, studies for the Genetic Epidemiology Consortium, we implemented three strategies for analysis, taking into account the known family histories of lung cancer. Susceptibility for lung cancer arises from a complex interplay between largely unknown genetic factors and smoking behavior. In order to optimize our ability to identify genetic factors for lung cancer we have recruited individuals with extensive family histories of lung cancer and also collected information about their smoking behaviors. For this study, we have modeled family history to identify individuals to select for sequencing using three approaches. First, we used an expert opinion approach in which multiple investigators evaluated pedigree structures with family history to reach a consensus priority in selecting individuals. Second we developed an approximation that assumes a low penetrance among noncarriers and uses known cancer status in first degree relatives. Third, we used the cancer, smoking behaviors and family information along with a likelihood that models penetrance according to genetic susceptibility and an interaction with smoking to estimate the probabilities individuals carry susceptibility factors. In this analysis we compare results among these methods. We evaluate effectiveness of these methods using simulation-based approaches.

Citation Format: Christopher Amos, Joan Bailey-Wilson, Susan Pinney, Maria de Andrada, Colette Gaba, Diptasri Mandal, Ming You, Margaret Spitz, Marshall Anderson. Optimal strategies for selecting samples for sequencing families with a common cancer: The Genetic Epidemiology of Lung Cancer Consortium. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A106.
Abstract A113: Regional variations in esophageal cancer incidence rates by census region in the United States, 1999-2008
Authors: Drahos Jennifer , Wu Manxia , Anderson William F. , Trivers Katrina F. , King Jessica , Rosenberg Philip S. , Eheman Christie R. , Cook Michael B.
Published: January 2014

Background: U.S. national cancer incidence estimates show a dramatic increase in esophageal adenocarcinoma (EA) and a simultaneous steady decrease in esophageal squamous cell carcinoma (ESCC). However, it is unknown whether substantial regional variations exist due to previous data limitations. Using the combined resource of NPCR and SEER, which covered 89% of the U.S. population, we assessed whether regional rates and trends significantly deviated from national estimates.

Methods: From NPCR-SEER, we extracted cancer case counts and populations for whites aged 45-84 years by calendar year, histology, sex, and census region for the period 1999-2008. We calculated age-standardized incidence rates (ASRs), annual percent changes (APCs), and male-to-female incidence rate ratios (MFIRRs).

Results: This analysis included 65,823 EAs and 27,094 ESCCs diagnosed during 778 million person-years. We observed significant geographic variability in EA and ESCC incidence rates and trends by census region, especially in men diagnosed with EA. The highest male ASRs for EA were observed in the Northeast (17.7 per 100,000) and Midwest (18.1 per 100,000), both of which were significantly higher (p<0.001) than the national estimate (16.0 per 100,000). The APC for men with EA in the Northeast was 62% higher than the national estimate (3.19% vs. 1.97%, P<0.001). The MFIRR for each histology remained fairly constant across calendar time, despite changes in incidence rates.

Conclusion: National estimates of esophageal cancer are not generalizable to specific census regions of the US. The stable MFIRRs may indicate predominant factors affecting esophageal cancer incidence rates are similar in men and women. These results underscore the importance of examining geographic and sex disparities in esophageal cancer.

Citation Format: Jennifer Drahos, Manxia Wu, William F. Anderson, Katrina F. Trivers, Jessica King, Philip S. Rosenberg, Christie R. Eheman, Michael B. Cook. Regional variations in esophageal cancer incidence rates by census region in the United States, 1999-2008. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A113.
Abstract A46: Role of the endocytic adaptor Epsin in cancer cell migration
Authors: Madhivanan Kayalvizhi , Aguilar R. Claudio
Published: January 2014

One of the most common links between cancer and endocytosis is defective internalization of Receptor Tyrosine Kinases, for example, linked to a deficit in endocytic proteins. This scenario leads to hypersignaling and in turn to malignant transformation. Nevertheless, there are also cases in which endocytic proteins, such as the epsin adaptors, are found upregulated in invasive cancers. Indeed, we demonstrated that overexpression of the epsins enhances cancer cell migration and invasion. Furthermore, depletion of epsins (by siRNA) led to impairment of cancer cell invasion. However, the different epsin paralogs varied in their capacity to enhance migration/invasion in the following order: epsin 3 > epsin2 >> epsin1. The epsin paralogs have a highly conserved Epsin N-terminal Homology or the ENTH domain (N-terminus) and a C-terminus where the most divergent regions are housed. While our data shows that both the ENTH domain and the C-terminus are required for enhancing migration, we speculate that the differential ability of the paralogs to migrate/invade lies in their less conserved C-terminus region.

This study aims to uncover the mechanism by which epsin overexpression leads to enhanced migration/invasion and to identify the regions of the epsin C-terminus which gives the paralogs their differential ability to enhance migration/invasion. Here we describe a systematic combinatorial approach for mapping the epsin determinants involved in localizing epsin at endocytic sites and required for its effect on cancer cell migration/invasion. Our data clearly shows that Clathrin binding motifs (out of the 4 types of endocytic determinants) are the strongest localization determinants of epsin2, however are not sufficient. Infact, 2 types of endocytic determinants are required for proper epsin2 localization suggesting co-operativity and redundancy. We also found that mutation of any 2 types of endocytic determinants can also reduce the ability of epsin2 to migrate as compared to the wild-type protein. Expanding the results obtained from epsin2 to epsin3 will reveal the similarities and differences between the paralogs. Taking together our findings and the requirement of these proteins for cancer cell invasion, we envision epsin2 and epsin3 as targets for novel anti-cancer and anti-metastatic approaches.

Citation Format: Kayalvizhi Madhivanan, R. Claudio Aguilar. Role of the endocytic adaptor Epsin in cancer cell migration. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A46.
Abstract A52: Tyrosine kinase activity of c-Abl is essential for p53 dependent transactivation of p21Waf1/Cip1
Authors: Udden S. M. Nashir , Satake Masanobu , Ikawa Shuntaro
Published: January 2014

c-Abl non-receptor tyrosine kinase is a pivotal upstream positive modulator in cellular response to DNA damage, which attributes to the activation of p53 tumor suppressor protein, hence the expression of the p53 target proteins promoting growth arrest and apoptosis. Nevertheless, the comprehensive function of c-Abl in the activation of p53 mediated by phosphorylation and acetylation is still largely elusive. Thus, in an attempt to determine the significance of tyrosine kinase activity of c-Abl in p53 activation, we examined the extent of p53 activation by exposing cells to Adriamycin (ADR). Under the presence of Abl kinase inhibitor, STI571, p53 dependent transactivation of p21 and Ser15/20 phosphorylation of p53 were markedly impaired. Furthermore, overexpression of the wild type c-Abl in ADR treated cells led to marked increase in p21 expression, whereas that of tyrosine kinase deficient c-Abl led to striking decrease. When U2OS cells were treated with increasing (0, 5, 10 & 15 μM) concentration of STI571, p21 expression gradually diminished with increasing concentration of STI571. In response to DNA damage Atm activates c-Abl, which in turn tyrosine phosphorylates and activates Atm making a positive feedback loop between Atm and c-Abl. We speculate the kinase activity of c-Abl is prerequisite to potentiate Atm activity by this feedback loop resulting in the augmented activation of p53. Preliminary experiments revealed that c-Abl abrogated deacetylation of p53 and Histone protein at p53 target genes promoter mediated by Histone deacetylases (HDACs). Detailed descriptions and significance of these observations will be discussed at the meeting.

Citation Format: S. M. Nashir Udden, Masanobu Satake, Shuntaro Ikawa. Tyrosine kinase activity of c-Abl is essential for p53 dependent transactivation of p21Waf1/Cip1. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A52.
Abstract A58: High Throughput Search for a Combination Cancer Preventive Treatment
Authors: Uray Ivan P. , Brown Powel H.
Published: January 2014

Identification of safer chemopreventive drugs is essential for the future of cancer preventive treatment. Although the feasibility for chemoprevention of estrogen receptor (ER) -positive breast cancers has been exemplified by the use of selective estrogen response modifiers (SERMs), we are still lacking preventive options for many other disease types, including breast cancers not dependent on ER status. Rexinoids are a class of agents that effectively reduce the incidence of both ER-positive and -negative tumors in animal models of breast cancer and thus may be better cancer preventive drugs than the current standard SERMs. However, significant side-effects at the effective clinical dose, including hypertriglyceridemia and weight gain, limit its generalized use. A phase II biomarker trial of the synthetic rexinoid, bexarotene (Targretin, LGD1069) demonstrated that bexarotene reduces expression of the proliferation markers Ki67 and Cyclin D1 in normal breast epithelium of postmenopausal women, suggesting that the cancer preventive effects of bexarotene are associated with its ability to elicit cell cycle blockade and inhibit proliferation of premalignant mammary epithelial cells. Here we hypothesize that the combination of repurposed drugs and some small molecule compounds with low dose rexinoid will minimize toxicity and result in effective anti-proliferative in premalignant cells. Therefore, we designed an image-based in vitro assay system to conduct high throughput screens to identify existing drugs and drug-like small molecules which enhance the growth suppressive effect of cancer preventive rexinoids. We used an automated 96 well platform to test the NIH clinical collection of drugs and a library of structurally diverse compounds (MayBridge Hitfinder) alone or in combination with 100nM bexarotene. Through multiparametric determination of cell counts, DNA content and cellular toxicity, we identified combination treatments of premalignant breast cells that fit the above criteria and report on dose-response studies and secondary screens for optimal dose and cell health. Validation of some of the candidate agents and plans for in vivo testing of their chemopreventive activity will be discussed.

Citation Format: Ivan P. Uray, Powel H. Brown. High-throughput search for a combination cancer preventive treatment. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A58.
Abstract A59: Combination of quercetin and tannic acid as a potential proteasome inhibitor for cancer chemoprevention
Authors: Chang Tsui-Ling , Wang Chi-Hsien
Published: January 2014

To look for oral proteasome inhibitors, the daily food is best source for cancer chemoprevention. A combination of active components from vegetables, coffee, tea, and fruit could be more efficient to inhibit 26S proteasome activities for preventing cancer diseases. Tannic acid and quercetin have been shown to strongly inhibit 26S proteasome activity, but the molecular target involved remains unknown. Overlay assay, peptide assay, western blot, and 2-D gels were used to assess the combination of quercetin and tannic acid as a potential inhibitor. Here, we demonstrated that the combination of quercetin and tannic acid synergistically suppresses chymotrypsin-like, caspase-like, and trypsin-like proteolytic activities and are tightly binding substrates. Quercetin plus tannic acid do not perturb the proteasome structure, inhibit the 26S proteasome affected by ubiquitin, ATP, or β-casein, and inhibit β-casein degradation by the 26S proteasome in vitro. Finally, inhibition of the proteasome by a combination of quercetin and tannic acid in Hep-2 cells resulted in induction of S5a at low dose, accumulation of ubiquitin, and the cleavage of pro-caspase-3, followed by induction of apoptotic cell death. Evaluating the combination of quercetin and tannic acid as an oral drug to prevent cancer may provide a pharmacological rationale to pursue preclinical trials of this combination.

Citation Format: Tsui-Ling Chang, Chi-Hsien Wang. Combination of quercetin and tannic acid as a potential proteasome inhibitor for cancer chemoprevention. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A59.
Abstract B14: Predicting prostate cancer: a novel, non-invasive approach
Authors: Roberts Matthew J. , Schirra Horst J. , Lavin Martin F. , Gardiner Robert A.
Published: January 2014

Introduction: Current approaches to the detection of prostate cancer require improvement. PSA and other methods fall short in discriminating between benign and malignant prostates, as well as defining the nature of disease.

We hypothesize that multiple markers, in non-invasive samples, can better detect prostate cancer and improve patient outcomes.

Methods: Discriminating mRNA markers in prostatic tissues were identified, and quantified using standard assays, to complement the non-coding gene PCA3. Complementary metabolomic analysis of ejaculate was performed using 500 MHz 1H-NMR spectroscopy.

Results: In 100 patients, RT-PCR for PCA3 and Hepsin from ejaculate in combination with serum PSA provided improved prediction compared with PSA alone. Further mRNA markers marginally improved these results.

Metabolomic analysis of ejaculate was initially confounded by contributions from buffer solution. Appropriate exclusion of confounders provided improved insight into sample and disease pathophysiology, and was combined with the molecular analysis.

Preliminary results have indicated that combining molecular and metabolomic data promise to improve detection rates. Results from this combined data analysis will be presented.

Furthermore, patients with initially negative prostate biopsies have been monitored for disease progression, with a number changing status over time. These findings have been analyzed and will also be presented.

Conclusion: Our results suggest that there is potential for non-invasive detection of prostate cancer. Current methods of detection are improved by combining clinical, genetic and metabolic markers from excreted biofluids. Further insight is provided into the pathophysiology of prostate cancer, which will further advance integration with imaging, as well as advancing the development of an accurate, non-invasive screening test for prostate cancer.

Citation Format: Matthew J. Roberts, Horst J. Schirra, Martin F. Lavin, Robert A. Gardiner. Predicting prostate cancer: A novel, noninvasive approach. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B14.
Abstract B29: Characterizing candidate breast cancer tumor suppressors: MTUS2 and LHX8
Authors: Fru Diane , Ruhl Victoria , Green Michael R.
Published: January 2014

Breast cancer is the most commonly occurring cancer among women in the United States. As with all other cancer types, breast cancer formation is the result of alterations in tumor suppressor genes, which regulate diverse cellular activities to prevent tumor development, and oncogenes, which promote tumor formation. In this study, we further characterized two candidate breast cancer tumor suppressor genes, MTUS2 and LHX8, and their role in breast cancer development. Soft agar assays showed that the knockdown of MTUS2 and LHX8 in MCF10AT cells led to increased colony formation compared to non-silencing control. Furthermore, through q-RT-PCR analysis, we found that the relative mRNA expression of MTUS2 and LHX8 is down-regulated in a panel of breast cancer cell lines compared to the pre-malignant breast epithelial cell line MCF10AT. Finally, when we ectopically expressed MTUS2 or LHX8 in MCF7 cells it resulted in slower proliferation of the cells compared to an empty vector control. Taken together, these results provide further information concerning the roles MTUS2 and LHX8 play in breast tumorigenesis. This study implicates two breast cancer tumor suppressor genes, which can provide a unique tool for identifying novel pathways involved in the formation of breast cancer.

Citation Format: Diane Fru, Victoria Ruhl, Michael R. Green. Characterizing candidate breast cancer tumor suppressors: MTUS2 and LHX8. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B29.

Note: This abstract was withdrawn after the Proceedings was printed and was not presented at the conference.
Abstract B56: Activation of Chk1 by Piperine causes cell cycle arrest and apoptosis in melanoma cells
Authors: Fofaria Neel , Srivastava Sanjay K.
Published: January 2014

The National Cancer Institute estimates that about 76,250 new cases of melanomas will be diagnosed in 2012 in the United States leading to at least 9810 related deaths. Therefore, novel strategies to control and treat melanoma are of prime importance. In this study, we determined the cytotoxic effects of piperine, a major constituent of black (Piper nigrum Linn) and long pepper (Piper longum Linn), in melanoma cell lines. Piperine treatment inhibited the growth of SKMEL-28 and B16-F0 cells in a dose and time-dependent manner. The growth inhibitory effects of piperine were mediated by cell cycle arrest of both the cell lines in G1 phase. The G1 arrest by piperine correlated with the down-regulation of cyclin D1 and induction of p21. Furthermore, this growth arrest was associated with DNA damage caused by piperine treatment as indicated by phosphorylation of H2A.X at Ser139, activation of ataxia telangiectasia and Rad3-related protein (ATR) and checkpoint kinase 1 (Chk1). Pretreatment with AZD 7762, a Chk1 inhibitor not only abrogated the activation of Chk1 but also piperine mediated G1 arrest. Furthermore, transfection of cells with Chk1 siRNA completely protected the cells from G1 arrest induced by piperine treatment. The G1 arrest by piperine was also confirmed with the down-regulation of E2F1 and decreased phosphorylation of retinoblastoma protein (Rb), indicating the inhibition of the dynamic transcription complex. In addition, apoptosis induced by piperine was associated with down-regulation of XIAP and Bid (uncleaved) and cleavage of Caspase-3 and PARP. In addition, our results showed that piperine treatment generated ROS in melanoma cells. Blocking ROS generation by Tiron prevented the cells from piperine mediated cell cycle arrest. Taken together, our results demonstrate that activation of Chk1 is required for piperine induced G1 phase cell cycle arrest. [Supported in part by R01 grants CA 106953 and CA 129038 awarded to S.K.S by National Cancer Institute, NIH]

Citation Format: Neel Fofaria, Sanjay K. Srivastava. Activation of Chk1 by Piperine causes cell cycle arrest and apoptosis in melanoma cells. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B56.
Abstract B98: Parity, breastfeeding and oral contraceptive use and risk of estrogen- and progesterone-negative breast cancer in the Breast Cancer Family Registry
Authors: Work Meghan E. , John Esther M. , Hopper John L. , Andrulis Irene L. , Terry Mary Beth
Published: January 2014

Introduction: Estrogen receptor (ER) and Progesterone receptor (PR) negative breast cancer (ER-PR-) is associated with poor prognosis. Little is known about modifiable risk factors, such as oral contraceptive use or breastfeeding, that can reduce risk of this cancer type; however, emerging evidence suggests that increased parity without breastfeeding may increase the risk of ER-PR- breast cancer, and that breastfeeding specifically will reduce this increased risk. Using population-based ascertained breast cancer cases from the Breast Cancer Family Registry (BCFR), we examined reproductive risk factors in relation to ER-PR- breast cancer.

Methods: Using data from 4,011 incident invasive breast cancer cases and 2,997 population-based controls from the BCFR, we evaluated the association between reproductive and hormonal risk factors with ER and PR status using unordered polytomous logistic regression, comparing two case groups, hormone receptor positive (HR+) breast cancers and ER-PR- breast cancer, to the control group.

Results: High parity without breastfeeding was positively associated only with ER-PR- tumors (odds ratio [OR] =1.57, 95% confidence interval [CI], 1.10-2.24, for ≥3 live births vs. nulliparity). High parity, when coupled with breastfeeding, was no longer associated with ER-PR- breast cancer (OR=0.93, 95%CI 0.71-1.22), and was inversely associated with all other HR+ cancers (OR=0.82, 95%CI 0.68-0.98). Parity (≥1 live birth vs. nulliparity), regardless of breastfeeding history, was protective against HR+ cancers only among postmenopausal women (OR=0.69, 95%CI 0.50-0.94). Oral contraceptive (OC) use was inversely associated with HR+ cancer (OR=0.82, 95%CI 0.69-0.96), but not associated with ER-PR- cancer. However, we found that OC use that commenced prior to 1975 was associated with an increased risk of ER-PR- cancer (OR=1.32, 95%CI 1.04-1.67), whereas OC use remained inversely associated with HR+ cancer only among women who began use in 1975 or later (OR=0.59, 95% CI 0.48-0.72).

Conclusion: As there are few modifiable factors for ER-PR- breast cancers, our findings lend further support to the potential that may be gained through greater promotion of breastfeeding to women at risk of ER-PR- breast cancers, and indicate that OC use is not a source of increased risk for these women.

Citation Format: Meghan E. Work, Esther M. John, John L. Hopper, Irene L. Andrulis, Mary Beth Terry. Parity, breastfeeding, and oral contraceptive use and risk of estrogen- and progesterone-negative breast cancer in the Breast Cancer Family Registry. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B98.
Abstract CN01-01: Inflammation links COPD/emphysema and lung cancer.
Authors: Houghton A. McGarry
Published: January 2014

Numerous epidemiological studies have consistently linked the presence of chronic obstructive pulmonary disease (COPD) to the development of lung cancer, independent of cigarette smoking dosage. The mechanistic explanation for this remains poorly understood. Progress toward uncovering this link has been hampered by the heterogeneous nature of the two disorders, with each being characterized by multiple sub-phenotypes of disease.

COPD can be broadly split into two disease processes, disease of the breathing tubes (airways disease) or destruction of the tiny air-sacks in the peripheral regions of the lung (airspace disease, or emphysema). A few insightful clinical studies have more clearly illustrated the nature of the link between COPD/emphysema and lung cancer by demonstrating that lung cancer risk is conferred by the emphysema component, and not by the airway component.

The current onus on the field is to identify mechanisms of disease common to both emphysema and lung cancer. There are several possibilities, including common genetic susceptibilities, competing forces with respect to apoptotic signaling, and shared inflammatory cell infiltrates.

The characteristic inflammatory cell infiltrate that is operative in emphysema pathogenesis and present within the tumor microenvironment, would appear to be the “low hanging fruit.” As such, this possible mechanistic link has received the most attention in this burgeoning field. Cigarette smoking produces a well-described infiltrate of macrophages, neutrophils, and T lymphocytes. Many of the products released by these cells'proteinases, reactive oxygen species, growth factors'are well known to fuel lung tumor growth, and in some cases, invasiveness as well. This microenvironment is not at all straightforward, however, as CD8+ T cells, present in emphysema, typically function in an antitumor fashion.

Going forward, the advancement of this field will require an improvement in disease models that allow for the simultaneous study of lung carcinogenesis within an emphysematous microenvironment. However, the potential to identify a common chemo-preventive target exists, and would be a welcome addition to clinicians, who have precious few options for patients afflicted with one or both of these diseases.

Citation Format: A. McGarry Houghton. Inflammation links COPD/emphysema and lung cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN01-01.
Abstract CN01-02: Epidemiology and pathogenesis of cancer in the setting of HIV infection
Authors: Casper Corey
Published: January 2014

Cancer has emerged as a leading cause of morbidity and mortality among HIV-infected persons worldwide. The incidence of cancer is increased exponentially in HIV-positive individuals, and in the United States it is estimated that nearly 10% of persons living with HIV will develop cancer in their lifetime. In this presentation, the epidemiology of HIV-associated malignancies in resource-rich and resource-limited settings will be reviewed, and the factors that predispose persons living with HIV to the development of cancer will be explored. The translatability of cancer screening and prevention practices from HIV-negative to HIV-positive patient populations remains unproven, but strategies for cancer prevention in HIV-positive individuals will be reviewed.

Citation Format: Corey Casper. Epidemiology and pathogenesis of cancer in the setting of HIV infection. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr CN01-02.