bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B41: Inhibition of beta-arrestin2-CARMA3 signaling axis impairs lysophosphatidic acid-induced ovarian cancer migration and invasion
Authors: Sun Jiyuan , Cai Jingli , Feng Yumei 
Published: May 2012

Abstract
Ovarian cancer is the fourth leading cause of cancer death among women in the United States. One of the biomarkers of ovarian cancer is lysophosphatidic acid (LPA). LPA is a type of G protein-coupled receptor ligand. It is strikingly elevated in 90% of ovarian cancer patients. Additionally, LPA receptors are aberrantly up-regulated in ovarian cancer patients. We have reported previously that a signaling axis consisting of beta-arrestin 2 and CARMA3 (CARD and MAGUK domain-containing protein 3) is indispensable in LPA-induced nuclear factor kappa B (NF-kappaB) activation in mouse embryonic fibroblast cells. NF-kappaB is an important transcription factor, which has been suggested to mediate LPA-induced ovarian cancer migration and invasion. However, it remains unknown whether the beta-arrestin2-CARMA3 signaling axis plays an important role in LPA-induced ovarian cancer cell migration and invasion. In the present study, using beta-arrestin 2 and CARMA3 shRNA, we knockdowned their protein expression levels in ovarian cancer cell lines. Consistent with previous reports, we found that down-regulation of beta-arrestin 2 and CARMA3 abolished LPA-induced IKK activity and NF-kappaB activation in ovarian cancer cells. In addition, in vitro transwell migration and matrigel invasion assays demonstrated that beta-arrestin 2 and CARMA3 shRNA significantly impaired LPA-induced ovarian cancer cell motility and invasiveness. Together, our results provide the evidence that β-arrestin 2 and CARMA3 serve as critical regulators in LPA-induced, NF-kappaB-mediated ovarian cancer migration and invasion. Therefore, we speculate that β-arrestin 2 and CARMA3 may represent attractive therapeutic targets for ovarian cancer and many other types of malignancies.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B41.
Abstract B53: Identifying functional polymorphisms that alter sulforaphane-induced gene expression via the NRF2 pathway
Authors: Chorley Brian N. , Wang Xuting , Campbell Michelle R. , Kleeberger Steven R. , Bell Douglas A. 
Published: May 2012

Abstract
Dietary isothiocyanates derived from the consumption of broccoli and other cruciferous vegetables have been shown to prevent cancer in various animal and clinical studies. Sulforaphane has been extensively used in mouse liver and lung studies to assess both anticancer effects and oxidant-induced gene transcriptional profiles. Sulforaphane imparts its antioxidant effects by activating the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway. NRF2 is a key transcriptional activator of antioxidant and phase II drug metabolism enzymes that regulate transcription by binding cis-acting antioxidant response elements (AREs) found in gene promoter regions. Since genetic factors, such as loss of function deletions in drug metabolism genes like glutathione-S-transferases, can influence the effectiveness of chemopreventive or chemotherapeutic agents, we hypothesized that single nucleotide polymorphisms (SNPs) within ARE sequences located in NRF2 target genes may alter sulforaphane-induced transcriptional regulation of these enzymes. To assess this, we exposed 60 unrelated, HapMap CEU cell lines to sulforaphane and measured global gene expression with Illumina gene expression arrays. We observed 2946 expression probes were either significantly induced (1436) or suppressed (1510) in at least 6 of the 60 cell lines by a fold change of 1.3 or greater (t-test with FDR correction, p&lt;0.09). Pathway analysis of induced genes indicated these genes are involved in oxidative stress response, apoptosis signaling and peroxide metabolism. SNP genotypes (identified by the HapMap project and our custom genotyping arrays) within a gene region were regressed against log2-transformed intensity values for each gene. Of the 11,566 SNPs that were significantly associated with gene expression after sulforaphane treatment (linear regression, p&lt;0.05), 972 SNPs were located within putative AREs identified by bioinformatics analysis and 55 SNPs were within 10kB of the transcriptional start site of a known ARE gene. To verify binding of NRF2 in these regions, NRF2-bound DNA isolated from a sulforaphane treated lymphoblastoid cell line was immunoprecipitated and analyzed by Agilent ChIP-on-chip. We observed that 23 of the 1027 selected SNPs were located near NRF2 bound regions. Three of these SNPs were located directly within ChIP-on-chip probe regions. This study provides promising SNP candidates for follow-up in molecular validation and clinical disease association studies. Functional SNPs that alter the binding potential and gene transactivation by NRF2 may help explain individual variation in the response to agents that modulate antioxidant and phase II enzyme regulation and subsequent clinical outcome.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B53.
Abstract B76: Protective role of Aquilegia vulgaris L extract against fumonisin-induced oxidative stress and cytotoxicity in rats
Authors: Hassan Aziza M. , Hassan Nabila S. , Mohamed Sherif R. , El-Nekeety Aziza A. , Abdel-Wahhab Mosaad A. 
Published: May 2012

Abstract
Fumonisins (FB) are mycotoxins produced by the fungus Fusarium verticillioides, which commonly infects corn and other crops worldwide. Exposure to FB is known to have toxic and carcinogenic effects in different animal species, and to express toxicity in cells via the induction of oxidative stress. The aim of the current study was to evaluate the protective effects of the ethanol extract of Aquilegia vulgaris L against the oxidative stress and the genotoxicity using the chromosomal aberrations in somatic cells assay and random amplified polymorphism DNA (RAPDPCR) in FBtreated rats. Sixty mature female Sprague-Dawley were divided into six treatment groups and treated for 4 weeks as follow: the control group, the group fed fumonisin-contaminated diet (200 mg/kg diet), the groups treated orally with the extract (5 and 10 mg/kg b.w) and the groups fed fumonisin contaminated diet and treated with the extract at the two doses. The results indicated that animals treated with fumonisin alone disturbs lipid profile in serum, increases Sa/So ratio, induces bone marrow cytotoxicity, increases DNA and RNA in liver accompanied with significant changes in histological picture. The extract alone at the two tested doses did not induce any significant changes in the biochemical or histological picture. The combined treatment showed significant improvements in all tested parameters and histological pictures in the liver tissues. Moreover, this improvement was more pronounced in the group received the high dose of the extract. It could be concluded that the ethanol extract of A. vulgaris induces its protective effect via increase the antioxidant capacity and the inhibition of lipid peroxidation.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B76.
Abstract B81: Colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis
Authors: Zhang Ling , Ren Xiaoyang , Alt Eckhard , Bai Xiaowen , Moyer Mary P. , Lynch Patrick M. , Wu Xiangwei 
Published: May 2012

Abstract
Cancer prevention is generally perceived as a long-term process and is inevitably associated with adverse effects. Here, we report the development of a therapy-like chemoprevention procedure that specifically targets premalignant tumor cells for apoptosis. This procedure is based on our finding that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of β-catenin lead to the repression of cellular caspase-8 (FLICE)-like inhibitory protein (cFLIP) expression through activation of c-Myc and that 9-cis-retinyl acetate (RAc) independently upregulates tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. We also show that in APC+/Min mice, TRAIL and RAc synergistically induce apoptosis specifically in intestinal polyps. Short-term non-treatment strongly inhibit tumor growth and promote survival. We further show that TRAIL and RAc have no detrimental effect on stem cells and TRAIL and RAc treatment induces significant cell death in human colon polyps. These results support that TRAIL and RAc represent a potential selective therapeutic approach for colon cancer chemoprevention by targeting APC-deficient cells for apoptosis.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B81.
Abstract B95: A novel small molecule, LLL12 inhibits STAT3 phosphorylation and activities and exhibits potent growth suppressive activity in human hepatocellular carcinoma cells
Authors: Zuo Mingxin , Lin Li , Liu Yan , DeAngelis Stephanie , Ball Sarah , Li Pui-Kai , Li Chenglong , Lin Jiayuh 
Published: May 2012

Abstract
Hepatocellular carcinoma is a major worldwide public health problem, and the third most frequent cause of cancer deaths after lung and stomach cancers. Hepatocellular carcinoma is a highly malignant tumor type with average survival rates that are currently less than 1 year following diagnosis. The etiology of hepatocellular carcinoma is still not well understood but involves a multi-step process of signaling protein dysregulation, which includes STAT3. The constitutive activation of STAT3 is frequently detected in clinical incidences of hepatocellular carcinoma and in more than 50% of human hepatocellular carcinoma cell lines but not in normal human hepatocytes. Constitutive STAT3 signaling contributes to hepatocellular carcinoma progression by promoting angiogenesis, survival, metastasis, and growth of hepatocellular carcinoma cells. Recent evidence suggests that the blockade of aberrant STAT3 signal pathway can be exploited as a therapeutic strategy for hepatocellular carcinoma. We have developed a novel small molecular STAT3 inhibitor LLL12 based on computer-aided rational design, which inhibits STAT3 activity by binding to its Src homology 2 (SH2) domain. LLL12 can inhibit STAT3 tyrosine 705 phosphroylation, STAT3 DNA binding activitivies. and prevent STAT translocation into the nucleus, thus decrease the transcription of target genes. And LLL12 also can inhibit IL-6 induced STAT3 phorsphorylation in Hep3B hepatocellular carcinoma cell. Our previous data show it can inhibit breast cancer (MDA-MB231 cells), brain tumor (U87 cells), and pancreatic cancer (PANC-1 cells) in vitro and in vivo. In this study, we report that LLL12 can selectively inhibit proliferation and induce apoptosis in SNU398, SNU387, Hep3B, and SNU449 hepatocellular carcinoma cells in vitro. Furthermore, the LLL12 can significantly inhibit tumor growth of SNU398 hepatocellular carcinoma cell line xenograft in nude mice at the dose of 5mg/kg. Collectively, our results show LLL12 could be used as a targeted drug candidate to target STAT3 for chemoprevention or treatment of Hepatocellular carcinoma in human.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B95.
Abstract CN10-02: Notch signaling in the progression of pancreatic cancer
Authors: Stanger Ben Z. 
Published: May 2012

Abstract
Notch signaling plays a crucial role during pancreatic development by maintaining pancreatic progenitor cells in an undifferentiated state. Notch signaling is activated in premalignant PanIN lesions (pancreatic intraepithelial neoplasia), and pancreatic cancer cell lines exhibit heightened sensitivity to Notch pathway inhibition. To determine whether the evolution from PanIN to adenocarcinoma requires Notch signaling, we performed a preventive trial in mice by inhibiting gamma secretase, an essential mediator of Notch signaling. Gamma secretase inhibition prevented the development of adenocarcinoma when animals bearing premalignant PanIN lesions were treated for several weeks. The drug was well tolerated. These results suggest that progression from premalignant PanIN lesions to pancreatic adenocarcinoma requires active Notch signaling. The Notch pathway may provide an attractive target for prevention or therapy in this treatment-refractory malignancy.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN10-02.
Abstract CN12-04: Prevention of skin cancer: Lessons from “Down Under.”
Authors: Green Adele C. , Williams Gail M. 
Published: May 2012

Abstract
Physical avoidance of intense/excessive exposure to sunlight is the mainstay of primary prevention of skin cancer. Since such exposure is sometimes unavoidable especially “Downunder,” we have studied adjunct protective measures to prevent basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma. In a 20-year community study in Queensland adults, the major adjunct measure that has emerged is regular sunscreen application. From 1992 to 1996, 1621 adult residents of the township of Nambour were randomly allocated to the sunscreen intervention: daily sunscreen application to head, neck, arms and hands, or the control arm: usual (discretionary) sunscreen use. (Allocation of a placebo sunscreen to the control group was unethical given the subtropical location.) After the trial, follow-up for primary BCC and SCC continued until 2004 and for melanoma until 2006 and sun exposure was also monitored. Available slides of melanomas were reviewed by two pathologists unaware of sunscreen allocation. No effect on incidence of basal cell carcinoma by sunscreen use was seen but the incidence of squamous-cell carcinoma tumors was significantly lower in the sunscreen intervention group than in the control group (Rate Ratio (RR) 0·61, 0·46–0·81). On follow-up 8 years after the sunscreen intervention ceased, a 35% decrease in overall incidence of SCC persisted in those randomly allocated to the intervention but no significant long-term reductions in incidence of BCC were observed. On follow-up 10 years after trial cessation, a significant reduction in melanoma was observed such that melanoma risk was halved in those allocated to the sunscreen intervention. The amounts of time spent outdoors on weekdays and weekend days were no different between the two trial-treatment groups. Certain dietary factors can also decrease skin cancer incidence, independently of sun exposure and phenotype. In those with past skin cancer, consumption of green leafy vegetables lowered risk of SCC by more than 50%, and dietary patterns characterized by low meat and fat intake similarly lowered SCC risk. In addition, the regular use of non-steroidal anti-inflammatory medications also substantially lowered the risk of SCC development. Thus SCCs appear amenable to prevention in adults by several adjunct means, while evidence regarding practical measures to complement basic sun protection measures for prevention of BCCs and melanoma is more limited.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN12-04.
Abstract CN12-05: Molecular aspects of melanoma
Authors: Thomas Nancy E. 
Published: May 2012

Abstract
The complex epidemiology of melanoma, variety of histologic subtypes, and presence of different genetic alterations has indicated for some time that melanoma is a heterogeneous disease. Subgroups of melanomas may develop along specific pathways resulting in complex risk factors, prognostic heterogeneity, and differing responses to treatments. Understanding and developing biomarkers for these pathways will be crucial for implementing appropriate interventions. Somatic alterations that are associated with these specific pathways include BRAF and NRAS mutations, which are mutually exclusive of each other, defining three melanoma subgroups (BRAF+/NRAS−, BRAF−NRAS+, and BRAF−/NRAS-). Number of nevi and ability to tan are associated with BRAF+ melanomas, while NRAS+ melanomas are also associated with number of nevi. BRAF−/NRAS− melanomas are associated with markers of chronic sun exposure, and exploration is under way to determine if BRAF+ and NRAS+ melanomas are associated with intermittent sun exposure and/or exposure at different ages. Melanocortin-1 receptor (MC1R) polymorphisms have been associated with BRAF-mutant melanoma in two Italian populations but not consistently in other populations. KIT mutations are also of interest and may define an additional pathway associated, in particular, with mucosal melanomas. These findings have strong implications for both targeted prevention and therapies, which could impact melanoma incidence and survival.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN12-05.
Abstract ED04-02: Phase 0 study design: Coming of age?
Authors: Limburg Paul J. 
Published: May 2012

Abstract
Despite ongoing advances in drug discovery science, anticancer agent development remains a laborious, time-consuming process. Discouragingly, the overall approval rate for new oncology drugs is approximately ∼ 5%, with estimated R & D costs ranging from $0.8–1.7 billion for each new agent. Lack of efficacy, suboptimal formulation, poor bioavailability and other factors contribute to the high pre-registration attrition rate, suggesting an urgent need for process enhancements that can facilitate earlier differentiation between viable and non-viable candidate compounds. In January 2006, the U.S. Food and Drug Administration (FDA) issued a guidance document on Exploratory IND Studies (a.k.a. phase 0 trials). In brief, phase 0 trials should (a) be conducted prior to traditional phase I, dose-limiting toxicity trials; (b) involve limited human exposure (usually ≤ 30 subjects); (c) have no therapeutic or diagnostic intent; and (d) be of relatively short duration (typically ≤ 7 days). Realistic goals for phase 0 trials include:replicate preclinical mechanism(s) of action in a human intervention trial;characterize initial pharmacokinetic/pharmacodynamic profiles;evaluate biodistribution patterns, based on imaging technologies.
Achieving one or more of these goals in phase 0 trials would permit better selection of active versus inactive compounds for further development. By design, phase 0 trials portend lower risks to human subject than traditional phase I trials. As such, fewer preclinical supporting data are required prior to conducting a phase 0 trial. The initial agent dose depends in part on the stated trial objectives, but should be no greater than 1/50th of the no-observed-adverse-effect level (NOAEL) estimated from animal toxicology testing. Validated pharmacodynamic assays, ideally with low variability in the molecular target, are suitable for application to phase 0 trials if the investigational agent can reasonably be expected to demonstrate target modulation at a non-toxic dose. Standard operating procedures for tissue collection and biospecimen handling should be defined in advance and revised as necessary based on results of the phase 0 trial. Chemoprevention agent development is uniquely challenged by the need to identify widely acceptable, minimally toxic compounds (even when chronically administered) that favorably affect carcinogenesis when measured against surrogate biomarkers, rather than direct cancer endpoints. Methods to identify bioavailable, pharmacodynamically active candidates earlier in the drug development cycle would offer clear advantages with respect to process efficiency, resource utilization and other parameters. Natural products (or derivatives thereof) represent an attractive source for chemoprevention agent discovery and, given their oftentimes demonstrated favorable safety profile at standard doses, provide an excellent opportunity to explore potential benefits gained through the phase 0 trial paradigm.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):ED04-02.
Abstract ED05-02: Diseases without borders: Partnering for prevention
Authors: Samet Jonathan M. 
Published: May 2012

Abstract
During the 21st century, ongoing epidemics of cancer and other non-communicable diseases can be anticipated with a high degree of certainty. The 20th century saw the rise of pandemics of non-communicable diseases, matching the burden of morbidity and mortality that had come with wellrecognized epidemics of infectious disease. These pandemics, including lung cancer and other cancers, coronary artery disease and atherosclerosis, and chronic obstructive pulmonary disease, were driven by causal factors with global reach: cigarettes and high-fat and high-calorie diets, for example. Beginning in the mid-20th century, epidemiological studies provided evidence that identified major causes of these epidemics and led to the start of disease control programs that are still in progress. Experience gained in addressing these epidemics led to evidence-based strategies at levels ranging from interventions with individuals to programs with global reach. Now, rates of these same chronic diseases are rapidly increasing in low- and middle-income countries where they were previously uncommon. Some of the increase reflects the spread of already well characterized risk factors, including smoking, high-fat and high calorie diets, and obesity.
This presentation focuses on research approaches to non-communicable diseases that will provide insights into factors driving the rising occurrence of these diseases around the world, while also offering evidence that can be quickly used to guide the development of control strategies. The presentation will cover historical patterns of disease occurrence, the global factors driving these epidemics, and the policy approaches to their control. Emphasis will be given to epidemiological study designs that can provide the evidence base needed for planning control programs, including multi-country studies which come with multiple design and implementation challenges. Examples will be drawn from the multi-country studies carried out by the International Agency for Research on Cancer (IARC), similar studies on the risks of tobacco smoking and air pollution, and pooling projects on cancer and cardiovascular disease.
Beyond the conduct of research, capacity building may be needed to develop capability to carry out multi-country protocols. Diverse models for capacity building have been applied; now distance-based approaches can facilitate the reach of academic institutions for training researchers. Networks of researchers can also be established as the internet now has true worldwide reach. Implementation of control programs remains a major barrier to disease control; unfortunately, the generation of research evidence does not necessarily lead to sound, evidence-based policies.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):ED05-02.