bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B22: Factors associated with community members' participation in a research registry
Authors: Skinner Celette Sugg , Tiro Jasmin A. , Bishop Wendy Pechero , Bruce Corinne
Published: May 2012

Introduction: It is important to provide community members - especially those from traditionally underserved groups - with equitable opportunities to participate in research. Volunteer registries have been employed to generate pools of potential participants. However, we know little about factors associated with participation in such registries.

Procedures: Bilingual research staff approached persons aged 18 and over attending the VIVA Dallas! Hispanic Exposition August 8–9, 2009, asking if they would complete a one-page health topics survey and receive, in return, a water bottle with our cancer center's logo. The survey, available in Spanish and English, measured age, sex, marital and parental status, race/ethnicity, country of birth, acculturation (Marin and Marin's 4-item scale), insurance coverage, access to and place of usual health care, and health topics of concern. One item asked, “May we contact you in the future for research studies?” and provided space for contact information for those who checked “yes”.

Data: The 1,183 survey completers were 64% female, 77% Hispanic, and 68% married or living as married. Most were parents (69%), ≤ 50 years old (68%), and were born outside the US (57%). Scores on the 4-item acculturation scale classified 45% with lower acculturation and 36% with higher acculturation; scores could not be calculated for the 19% with missing data. Some type of insurance coverage was reported by 40% (with 19% missing) and 43% reported access to usual health care (with 17% missing). Most frequently cited health topics of concern were diabetes (53%), healthy eating (32%) and managing stress (31%). Cancer was mentioned by 20%, with breast being the most-cited cancer type. Overall, 63% indicated agreement to be contacted for future studies. Agreement was significantly associated (all p<.01) with: age less than 50, female sex, having ever been married, being the parent of at least one child, Hispanic ethnicity, birth outside the US, lower acculturation score, no insurance coverage, and no place for usual health care.

Conclusions: Among attendees at Dallas' largest Hispanic community event, interest in completing the survey was high. The majority of survey completers (63%) agreed to be contacted for future studies. People most likely to agree to future contact represented groups often not included in studies - those born outside the US, with lower acculturation scores, and no health insurance or source of regular health care. Use of registries generated through community events such as VIVA Dallas! may help to address disparities in access to and participation in cancer control research.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B22.
Abstract B26: Cancer prevention clinical trials: Assessing for disparities in recruitment in Hawaii
Authors: Bantum Erin O. , Cheng Iona , Cassel Kevin , Ka'opua Lana Sue , Berenberg Jeffrey
Published: May 2012

A key concern of clinical trials of cancer is improving the participation rates of minority populations that are often underrepresented and have high rates of disease. In particular, identifying the underlying factors that contribute to the underrepresentation of minorities is essential for developing improved recruitment strategies—this is especially important for prevention trials of cancer that may ultimately translate to reducing the burden of disease in the population. To identify disparities in cancer prevention trials in Hawaii, we compared participation rates across racial/ethnic groups for breast and prostate cancer prevention trials. We then examined the methods of recruitment for each trial. The following four prevention trials were included in our assessment: the Breast Cancer Prevention Trial (BCPT), the Prostate Cancer Prevention Trial (PCPT), and the Study of Tamoxifen and Raloxifene (STAR). We identified gender differences in the participation rates of Native Hawaiians. Among 272 female participants in the STAR and BCPT trials, 10.3% (n = 28) were Native Hawaiian. In contrast, among 213 male participants in the SELECT and PCPT studies, only 5.2% (n = 11) were Native Hawaiian. The ethnic breakdown of the state during the approximate time of recruitment (2000) was as follows: African American 2.4%, Caucasian 24.3%, Chinese 7.4%, Filipino 16.5%, Hawaiian 19.8%, Japanese 18.9%, Korean 2.4%, Other ethnicities 8.4% (US Census, 2000). In these trials differing recruitment strategies were used. For example, in the SELECT trial a targeted direct mailing campaign to men 50 years of age or older (27.6% of sample), whereas in the STAR trial physician referral was the primary source of participation (59.0%). While these analyses do not speak to what specific strategies were most beneficial for a given racial/ethnic group, it is important to note that there was a higher likelihood of recruiting Native Hawaiian women when they were referred to the trial by their physician. Understanding the importance of the relationship between the study participant and the referral agent is just one strategy that will be examined in our future work. Researchers attempting to recruit African Americans at a rate of 20% for clinical trials (Cook at al., 2005) found that a diligent effort aimed at expanding the eligibility recruitment for African American men and the provision of more resources to particularly target this group were strategies that helped decrease disparities in recruitment. Given the multi-ethnic and multi-cultural nature of Hawai'i there are a wide range of practices and beliefs that need to be considered and incorporated in clinical trial recruitment. Our ultimate goal is to improve the participation rates of Native Hawaiians in clinical trials of cancer prevention.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B26.
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

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

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<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<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

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

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

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

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

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

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

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

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.
Abstract KN01-03: Keynote Address: Personalized targeted chemoprevention: Opportunities and challenges
Authors: Hong Waun Ki
Published: May 2012

Epithelial cancers are a major killer worldwide. The epithelial cancers develop by a multistep process through premalignant lesions to invasive cancer at multiple sites through a process of field carcinogenesis. Unfortunately, many chemoprevention trials conducted in various disease sites have failed to demonstrate any efficacy to prevent cancer other than hormone targeted prevention trials in breast and prostate cancers.

Our group has demonstrated proof of principle of the efficacy of targeted chemopreventive agents in combination therapy reversing phenotypic changes of laryngeal premalignant lesions but observed persistent genotypic changes; thus, the obvious goal is the elimination of genetic scars to prevent cancer effectively.

The human genome project was completed in 2001 and many new genes have been discovered which have been implicated in cancer in general. A major challenge is translating these gene discoveries to clinical benefit for both prevention and therapy. Now, the hallmarks of cancer have been elucidated and we have a better understanding of the interactions between cancer cells and microenvironment and are able to integrate signaling pathways leading to cancer progression.

The other important challenge is identifying the highest risk cohort for primary and second primary cancers through clinical, epidemiologic, and genetic variables to create a risk model such that, ultimately, we can target this group with personalized targeted chemoprevention therapy.

In order to achieve the goals above, we must understand fully the molecular and genetic fingerprints of premalignant lesions from different organ sites and the alteration of pathways which are the driving force of cancer progression. These pathways can be targeted and perturbed by agents matched to alter the molecular defects.

Personalized targeted chemoprevention has enormous potential to make an impact from a public health point of view. To do this, we must first develop and validate the efficacy of personalized targeted therapy agents in metastatic settings, then migrate, in reverse fashion, into the early disease arena, such as the adjuvant setting, and then tackle premalignant lesions to eradicate aberrant clones and/or undermine clonal activity so that cancer can be either prevented or delayed.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):KN01-03.
Abstract PR-01: Vitamin D receptor expression is inversely associated with prostate cancer progression
Authors: Hendrickson Whitney , Kasperzyk Julie , Flavin Richard , Fiorentino Michelangelo , Lis Rosina , Fiore Christopher , Penney Kathryn , Ma Jing , Stampfer Meir , Loda Massimo , Mucci Lorelei , Giovannucci Edward
Published: May 2012

Background: Vitamin D is inversely associated with risk of several malignancies. Circulating vitamin D interacts with the vitamin D receptor (VDR) at the cellular level to inhibit proliferation, increase apoptosis and decrease angiogenesis. Thus, although vitamin D levels appear to be unrelated to total prostate cancer incidence, VDR levels in tumor tissue may influence prostate cancer prognosis.

Methods: We examined the immunohistochemical expression of VDR on archival tumor tissue from 841 prostate cancer cases diagnosed between 1982 and 2004 within two ongoing, prospective cohorts: the Physicians' Health Study and Health Professionals Follow-up Study. VDR expression was measured quantitatively using the CRi Vectra™ system. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of VDR expression with lethal prostate cancer (N=73) through 2008. On a subset of cases, we also examined correlation of tumor VDR expression with circulating 25(OH)D3 and 1alpha,25(OH)2D3 measured at baseline (N=84) in 1982 and two SNPs in VDR: Fok1 and bsm1 (N=140).

Results: Men with high tumor VDR expression had significantly lower Gleason score, lower prostate specific antigen (PSA) levels at diagnosis, and were less likely to have advanced tumor stage (p=0.008, p=0.012, p=0.001, respectively). Compared to the lowest quartile, men in the highest quartile of VDR expression were at significantly lower risk of developing lethal prostate cancer (age-adjusted HRs across quartiles Q2=0.95, 95% CI: 0.51–1.79; Q3=0.93, 95% CI: 0.49–1.76; Q4 = 0.23, 95% CI:0.09–0.55). This association was attenuated (HRQ4vsQ1 = 0.42, 95% CI: 0.16–1.09) after further adjustment for pathological tumor stage, Gleason grade, and PSA level at diagnosis. Tumors expressing high levels of VDR had modest downregulation of cell proliferation as measured by Ki67 (r=-0.11). Moreover, expression of estrogen receptor alpha (r=0.40, p<0.001) and androgen receptor (r=0.41, p<0.001) were positively correlated with VDR expression. Neither prediagnostic plasma vitamin D levels nor gene variants in VDR were associated with VDR protein expression in tumors.

Conclusion: In this large prospective study, men with tumors that demonstrated upregulation of VDR had significantly improved clinical features and reduced risk of lethal prostate cancer. In line with experimental studies, the positive correlation between VDR expression, and androgen receptor and estrogen receptor provides evidence that that VDR acts in an androgen- and/or estrogen-dependent manner. These data highlight the potential role of the vitamin D system in preventing prostate cancer progression.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):PR-01.
Abstract PR-03: Genetic variations in microRNA biogenesis genes as predictors for risk of second primary tumor (SPT) and/or recurrence in patients with early-stage head and neck cancer
Authors: Zhang Xiaofan , Yang Hushan , Lee J. Jack , Kim Edward , Lippman Scott M. , Khuri Fadlo R. , Spitz Margaret R. , Lotan Reuben , Hong Waun K. , Wu Xifeng
Published: May 2012

Second primary tumors (SPTs) and local-regional recurrence negatively impact the prognosis of patients with curatively treated early-stage head and neck cancer. Genetic variations in microRNA (miRNA) biogenesis genes have been found to be associated with the risk of multiple solid tumors. Thus, we hypothesized that these variations were also associated with the risk of SPT/recurrence in patients with early-stage head and neck cancer. We performed a nested case-control study including 150 early-stage head and neck cancer patients with SPT/recurrence and 300 patients without SPT/recurrence. We genotyped 71 tagging and potentially functional single nucleotide polymorphisms (SNPs) from eight miRNA biogenesis pathway genes (RNASEN, DGCR8, DICER1, EIF2C1, DDX20, GEMIN4, RAN, XPO5). Seven SNPs in RNASEN, one in XPO5, and one in RAN were significantly associated with the risk of SPT/recurrence. The most significant SNP was rs7735863, an intronic SNP in RANSEN. The variant-containing genotypes of this SNP were associated with a 1.72-fold increased risk (95% confidence interval [CI], 1.16–2.57; P=0.0076). A combined analysis showed that compared with the patients without any unfavorable genotypes, the SPT/recurrence risk was increased 1.50- (95% CI, 1.02–2.22) and 2.69-fold (95% CI, 1.59–4.53) for those with one and two unfavorable genotypes, respectively (P for trend<0.001). Survival tree analysis further identified potential higher-order interactions and categorized the study subjects into different risk groups. Compared to the low-risk group with an event-free median survival time (MST) over 96 months, patients in the high-risk group had a 5.02-fold increased risk (95% CI, 2.70–9.31; P=3.20×10−7) and an event-free MST of 31.4 months (log rank P=1.25 − 10−7). Our results suggest that genetic polymorphisms within the miRNA biogenesis pathway may be used individually and jointly to predict the risk of SPT/recurrence of early-stage head and neck cancer patients.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):PR-03.
Abstract PR-08: Body mass index and breast cancer outcomes in older breast cancer survivors
Authors: Bosco Jaclyn L.F. , Silliman Rebecca A.
Published: May 2012

Obesity may increase the risk of breast cancer and decrease survival in postmenopausal women through higher levels of circulating estrogen. The mortality risk is greater in younger women, but studies of women ≥ 65 years are limited. Consenting women ≥ 65 years at incident diagnosis of stage I (tumor ≥ 1 cm), stage II, or stage IIIA primary breast cancer from Los Angeles, Minnesota, North Carolina, or Rhode Island were interviewed by telephone 3 months (baseline) after their definitive surgery (N=658) and were followed annually for 9 years unless death, loss to follow-up, or refusal to continue participation occurred. BMI was calculated using weight (kilograms [kg]) and height (meters [m]) reported at baseline (BMI 25–29 kg/m2 = overweight; BMI ≥ 30 kg/m2 = obese). Women with a healthy BMI (< 25 kg/m2) comprised the reference group. Recurrence was collected during follow-up interviews. Death was confirmed by a Social Security Death Index search through March 2009 and date and cause of death were collected from the National Death Index through 2004. Demographic characteristics (age, race, marital status, education, geographic location, and Charlson Comorbidity Index [CCI]) were collected at baseline. Breast cancer tumor (stage, histologic grade, estrogen receptor expression) and treatment (primary therapy, adjuvant chemotherapy receipt, adjuvant tamoxifen receipt) characteristics were collected from medical records. Of our cohort, 34% were overweight and 21% were obese (mean BMI, 25.7 kg/m2). The majority of overweight women were 70–74 years old (29%), had a CCI of 0 (62%), and completed college or higher (53%); obese women were mostly 65–69 years (34%), had a CCI of 2 (13%) and only completed up to high school (40%). Women who were overweight (Odds Ratio [OR]=1.5; 95% Confidence Interval [CI]=0.8, 2.7) or obese (OR=1.6; 95% CI=0.8, 3.1) had an increased the risk of recurrence compared with women with a healthy BMI. Being overweight was not associated with breast cancer-specific mortality or allcause mortality. Obese women had nearly a twofold increased risk of dying from breast cancer (OR=1.9; 95%CI=0.7, 5.0); obesity was weakly associated with the risk of dying from any cause (OR=1.2; 95%CI=0.7, 1.8). Weight at baseline and 6 years later were consistently reported by the women in our study. Since women do not tend to overestimate their weight, our results conservatively estimate the effect of obesity on breast cancer outcomes. Unlike many previous studies, we had detailed information regarding primary and adjuvant treatment, which are important in estimating the risk of breast cancer recurrence and mortality. Although our data are compatible with a 20–30% decreased risk of breast cancer outcomes, our findings suggest higher body mass after breast cancer diagnosis is associated with negative outcomes in older women. Achieving or maintaining a healthy BMI after definitive surgery may improve breast cancer prognosis.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):PR-08.
Complementary Foods and Flavor Experiences: Setting the Foundation
Authors: Mennella Julie A. , Trabulsi Jillian C.
Published: May 2012

Increased fruit and vegetable consumption early in life may lead to life-long intake of fruits and vegetables, which in turn may be beneficial for weight control and other health outcomes in later life. Although health officials worldwide recommend delaying solid foods until 6 months of age, younger infants often receive solid food, which may affect later obesity rates. The timing of introduction to solid foods is important both nutritionally and developmentally and may affect acceptance of foods both in infancy and later in life. Infants can clearly discriminate the flavors of different fruits and vegetables. Repeated flavor experiences promote the willingness to eat a variety of foods: infants will consume more of foods that have a familiar flavor and are more accepting of novel flavors if they have experience with flavor variety. Many flavors that the mother either ingests or inhales are transmitted to her milk and/or amniotic fluid. Mothers can help the transition from a diet exclusively of milk or formula to a mixed diet by providing the infant familiar flavors in both milk or formula and solid foods. Exposure to a variety of flavors during and between meals appears to facilitate acceptance of novel foods. Providing novelty in the context of a familiar food might prove to be an optimal combination to progressively accustom infants to a diversity of novel foods. When repeatedly exposing infants to flavors of some vegetables that have bitter tastes, mothers should focus not on infants’ facial expressions but on their willingness to eat the food and should continue to provide repeated opportunities to taste the food. Introducing children repeatedly to individual as well as a variety of fruits and vegetables, both within and between meals, might help them be more accepting of fruits and vegetables, which is difficult to enhance beyond toddlerhood.
An Acute Infusion of Lactic Acid Lowers the Concentration of Potassium in Arterial Plasma by Inducing a Shift of Potassium into Cells of the Liver in Fed Rats
Authors: Cheema-Dhadli S. , Chong C.-K. , Kamel K.S. , Halperin M.L.
Published: May 2012

Background: Potassium (K+) input occurs after meals or during ischemic exercise and is accompanied by a high concentration of L-lactate in plasma (PL-lactate). Methods: We examined whether infusing 100 µmol L-lactic acid/min for 15 min would lead to a fall in the arterial plasma K+ concentration (PK). We also aimed to evaluate the mechanisms involved in normal rats compared with rats with acute hyperkalemia caused by a shift of K+ from cells or a positive K+ balance. Results: There was a significant fall in PK in normal rats (0.25 mM) and a larger fall in PK in both models of acute hyperkalemia (0.6 mM) when the PL-lactate rose. The arterial PK increased by 0.8 mM (p < 0.05) 7 min after stopping this infusion despite a 2-fold rise in the concentration of insulin in arterial plasma (PInsulin). There was a significant uptake of K+ by the liver, but not by skeletal muscle. In rats pretreated with somatostatin, PInsulin was low and infusing L-lactic acid failed to lower the PK. Conclusions: A rise in the PL-lactate in portal venous blood led to a fall in the PK and insulin was permissive. Absorption of glucose by the Na+-linked glucose transporter permits enterocytes to produce enough ADP to augment aerobic glycolysis, raising the PL-lactate in the portal vein to prevent postprandial hyperkalemia.
Dabigatran etexilate and concomitant use of non-steroidal anti-inflammatory drugs or acetylsalicylic acid in patients undergoing total hip and total knee arthroplasty: No increased risk of bleeding
Authors: Kurth Andreas , Clemens Andreas , Noack Herbert , Eriksson Bengt , Caprini Joseph , Friedman Richard
Published: May 2012

Patients undergoing total hip or knee arthroplasty should receive anticoagulant therapy because of the high risk of venous thromboembolism. However, many are already taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA) that can have antihaemostatic effects. We assessed the bleeding risk in patients treated with thromboprophylactic dabigatran etexilate, with and without concomitant NSAID or ASA. A post-hoc analysis was undertaken of the pooled data from trials comparing dabigatran etexilate (220 mg and 150 mg once daily) and enoxaparin. Major bleeding event (MBE) rates were determined and odds ratios (ORs) generated for patients who received study treatment plus NSAID (half-life ≤12 hours) or ASA (≤160 mg/day) versus study treatment alone. Relative risks were calculated for comparisons between treatments. Overall, 4,405/8,135 patients (54.1%) received concomitant NSAID and 386/8,135 (4.7%) received ASA.ORs for the comparison with/without concomitant NSAID were 1.05 (95% confidence interval [CI] 0.55–2.01) for 220 mg dabigatran etexilate; 1.19 (0.55–2.55) for 150 mg; and 1.32 (0.67–2.57) for enoxaparin. ORs for the comparison with/without ASA were 1.14 (0.26–5.03); 1.64 (0.36–7.49); and 2.57 (0.83–7.94), respectively. For both NSAIDs and ASA there was no significant difference in bleeding between patients with and without concomitant therapy in any treatment arm. Patients concomitantly taking NSAIDs or ASA have a similar risk of MBE to those taking dabigatran etexilate alone. No significant differences in MBE were detected between dabigatran etexilate and enoxaparin within comedication subgroups, suggesting that no increased major bleeding risk exists when dabigatran etexilate is administered with NSAID or ASA.

Investigation performed at multiple centres participating in the RE-MODEL™, RE-NOVATE®, and RE-MOBILIZE® trials.
Propranolol as antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia
Authors: Albiñana Virginia , Recio-Poveda Lucía , Zarrabeitia Roberto , Bernabéu Carmelo , Botella Luisa
Published: May 2012

The β-blocker propranolol, originally designed for cardiological indications (angina, cardiac arrhythmias and high blood pressure), is nowadays, considered the most efficient drug for the treatment in infantile haemangiomas (IH), a vascular tumour that affects 5–10% of all infants. However, its potential therapeutic benefits in other vascular anomalies remain to be explored. In the present work we have assessed the impact of propranolol in endothelial cell cultures to test if this drug could be used in the vascular disease hereditary haemorrhagic telangiectasia (HHT). This rare disease is the result of abnormal angiogenesis with epistaxis, mucocutaneous and gastrointestinal telangiectases, as well as arteriovenous malformations in several organs, as clinical manifestations. Mutations in Endoglin (ENG) and ACVLR1 (ALK1) genes, lead to HHT1 and HHT2, respectively. Endoglin and ALK1 are involved in the TGF-β1 signalling pathway and play a critical role for the proper development of the blood vessels. As HHT is due to a deregulation of key angiogenic factors, inhibitors of angiogenesis have been used to normalise the nasal vasculature eliminating epistaxis derived from telangiectases. Thus, the antiangiogenic properties of propranolol were tested in endothelial cells. The drug was able to decrease cellular migration and tube formation, concomitantly with reduced RNA and protein levels of ENG and ALK1. Moreover, the drug showed apoptotic effects which could explain cell death in IH. Interestingly, propranolol showed some profibrinolytic activity, decreasing PAI-1 levels. These results suggest that local administration of propranolol in the nose mucosa to control epistaxis might be a potential therapeutic approach in HHT.