bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Premenopausal Women
Authors: Fabian Carol J. , Kimler Bruce F. , Phillips Teresa A. , Box Jessica A. , Kreutzjans Amy L. , Carlson Susan E. , Hidaka Brandon H. , Metheny Trina , Zalles Carola M. , Mills Gordon B. , Powers Kandy R. , Sullivan Debra K. , Petroff Brian K. , Hensing Whitney L. , Fridley Brooke L. , Hursting Stephen D.
Published: October 2015

Higher intakes of the omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) have been variably associated with reduced risk of premenopausal breast cancer. The purpose of this pilot trial was to assess feasibility and explore the effects of high-dose EPA and DHA on blood and benign breast tissue risk biomarkers before design of a placebo-controlled phase IIB trial. Premenopausal women with evidence of hyperplasia ± atypia by baseline random periareolar fine needle aspiration were given 1860 mg of EPA + 1500 mg of DHA ethyl esters daily for 6 months. Blood and benign breast tissue were sampled during the same menstrual cycle phase prestudy and a median of 3 weeks after last dose. Additional blood was obtained within 24 hours of last dose. Feasibility, which was predefined as 50% uptake, 85% retention, and 70% compliance, was demonstrated with 46% uptake, 94% completion, and 85% compliance. Cytologic atypia decreased from 77% to 38% (P = 0.002), and Ki-67 from a median of 2.1% to 1.0% (P = 0.021) with an increase in the ratio of EPA + DHA to AA in erythrocyte phospholipids but no change in blood hormones, adipokines, or cytokines. Exploratory breast proteomics assessment showed decreases in several proteins involved in hormone and cytokine signaling with mixed effects on those in the AKT/mTOR pathways. Further investigation of EPA plus DHA for breast cancer prevention in a placebo-controlled trial in premenopausal women is warranted. Cancer Prev Res; 8(10); 912–21. ©2015 AACR.

See related article, p. 922.
Abstract A07: Methylation of RARB in prediagnosis benign tissue and risk of disease progression in men subsequently diagnosed with prostate cancer
Authors: Rybicki Benjamin , Jankowski Michelle , Do Kieu , Chitale Dhananjay , Trudeau Sheri , Rundle Andrew , Belinsky Steven , Tang Deliang
Published: October 2015

We previously reported results from a case-control study nested in a large hospital-based cohort of men identified over a 12-year period (1990-2002) that gene promoter hypermethylation in histopathologically benign prostate specimens is a marker of prostate cancer risk (Tang et al. J Urol 2013). Whether methylation in pre-diagnostic benign prostate tissue can also predict subsequent disease prognosis has not been studied. Therefore, we estimated hazard ratios (HRs) for biochemical recurrence (BCR), defined as two successive prostate-specific antigen increases after definitive treatment, associated with methylation status of the two genes we found associated with prostate cancer risk: retinoic acid receptor-β (RARB) and adenomatosis polyposis coli (APC). Follow-up data were from a subset of the cases (n=394) that were part of our aforementioned nested prostate cancer case-control study of gene promoter methylation status of five genes measured in pre-diagnostic benign biopsy specimens. Overall, after adjusting for known clinical risk factors for prostate cancer progression (advanced grade, advanced stage, high prostate-specific antigen (PSA)), neither methylation of the APC or the RARB genes was associated with a significantly increased risk of BCR, but risk associated with RARB methylation was elevated (HR=1.30; 95% CI= 0.93-1.83). This risk was higher in Whites (HR=1.44; 95% CI= 0.92-2.25) compared with African Americans (HR=1.22; 95% CI= 0.71-2.12), but differences by race were not significant. In additional stratified analyses, we found that while associations with APC methylation did not differ between strata, RARB methylation showed significantly increased risk of BCR in specific substrata; specifically men with high PSA at time of diagnosis (HR=1.73; 95% CI=1.13–2.64) and men in whom methylation did not occur in the four other genes under study (HR=1.82; 95% CI=1.14–2.93). In conclusion, we show for the first time that methylation events occurring before onset of prostate cancer may predict the course of subsequent cancer in defined patient groups. These findings may have important clinical decision making implications in terms of both identifying aggressive prostate cancer at its earliest stages and also avoiding unnecessary additional diagnostic biopsies.

Citation Format: Benjamin Rybicki, Michelle Jankowski, Kieu Do, Dhananjay Chitale, Sheri Trudeau, Andrew Rundle, Steven Belinsky, Deliang Tang. Methylation of RARB in prediagnosis benign tissue and risk of disease progression in men subsequently diagnosed with prostate cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A07.
Abstract A24: Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer
Authors: Lord Simon R. , Patel Nilay , Liu D. , Fenwick J. , Frezza C. , Costa S. Henriques da , Gaude E. , Zhang Q. , Wakelam M. , Gleeson F. , Haider S. , Buffa F. , Harris A. L.
Published: October 2015

There is great interest in the effects on cancer metabolism of the diabetes drug, metformin and its potential as a cancer treatment. Despite intense investigation it is still not clear as to its metabolic effects on primary human cancer in vivo. 41 patients with primary breast cancer were recruited to a ‘window of opportunity study’ prior to neoadjuvant chemotherapy. Before and after 2 weeks of metformin, dynamic 18F-FDG PET-CT scans were carried out, breast core biopsies of the primary tumour taken for RNASeq, metabolomics and immunohistochemistry analysis and host serum metabolic markers assessed.

Metabolomic mass spectrometry analysis revealed an increase in the ADP/ATP and AMP/ATP ratio (fold change 8.6 and 24.9, respectively, p = 0.07 and p = 0.14) after metformin treatment.

RNA sequencing of the first 21 paired samples showed upregulation of many genes encoding components of complex 1, and the TCA cycle, glutaminolysis, and glycolysis pathways. Several genes encoding for glucose and glutamine transport were amongst those most consistently upregulated, including GLUT1, SLC38A1 and SLC7A5 (all p<0.0001).

Dynamic PET-CT analysis of the first 17 paired scans demonstrated a trend toward a decrease in the variable K2 post-metformin (an estimate of 18F-FDG efflux from tumour intracellular pool back to blood), but with much variability between paired scans (0.70±0.11 vs 0.51±0.05 (p=0.14)).

There was a decrease in serum C-peptide (0.56±0.04nmol/L vs 0.48±0.02nmol/L, pre- and post-metformin, p=0.003) consistent with reduced host insulin secretion. This is the first study in the clinical setting to show that metformin can cause an energy stress in cancer cells. The effect on mRNA expression was compatible with direct mitochondrial effects on the cancer cell leading to upregulation of the glutaminolysis and glycolysis pathways. The decrease in efflux of radiolabelled glucose may indicate retention of glucose possibly secondary to changes in blood glucose availability. We expect this study will help define biomarker development and future treatment strategies for metformin, in particular potential combination therapy.

Note: This abstract was not presented at the conference.

Citation Format: Simon R. Lord, Nilay Patel, D. Liu, J. Fenwick, C. Frezza, S. Henriques da Costa, E. Gaude, Q. Zhang, M. Wakelam, F. Gleeson, S. Haider, F. Buffa, A. L. Harris. Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A24.
Abstract B11: An efficient resource to accelerate research into the cause and prevention of breast cancer: The Army of Women
Authors: Love Susan M. , Eshraghi Leah D.
Published: October 2015

Background: It is well established that more research into the cause and prevention of breast cancer is needed. While studies are done in cell lines and lab animals, translation of findings to women is often delayed due to difficulty in recruitment. To address this problem, the Dr. Susan Love Research Foundation formed the Army of Women® (AOW); an online recruitment resource designed to partner women with researchers in order to accelerate breast cancer research.

Methods: Researchers submit a proposal to the Dr. Susan Love Research Foundation's Scientific Advisory Committee. If a study is accepted, a mass e-mail describing the study procedures and inclusion/exclusion criteria is sent to the entire AOW database. Women sign up at www.armyofwomen.org to join and receive AOW e-mails about breast cancer research studies. Women self-select based on interest and study criteria, and undergo a secondary online screening before contact information is passed on to the researcher for the enrollment process.

Results: Over 376,000 women have signed up, including survivors and women without a history of breast cancer, ranging from ages 18 to 100, representing all 50 US states and 49 countries. To date, the AOW has recruited for 87 studies. The diversity of the AOW members has proved beneficial for many studies, such as those needing to enroll racial/ethnic minorities, women of varying sexual orientations, or young survivors.

A secondary goal of the AOW is to assist researchers new to research with human subjects. The AOW has successfully helped researchers cross the chasm, coaching them on what it takes to transition their research from animal models to human subjects.

Conclusions: The AOW has proved to be a successful resource for scientists to accelerate accrual, expand the number and diversity of their subject population and to obtain exactly the type of specimens they need when they need it. This partnership between women and scientists has revolutionized research and accelerated efforts to eradicate breast cancer. The public is ready and willing to partner with the research community to find the answers to urgent clinical problems.

Citation Format: Susan M. Love, Leah D. Eshraghi. An efficient resource to accelerate research into the cause and prevention of breast cancer: The Army of Women. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B11.
Abstract B45: A pilot trial of dietary fish and ω-3 fatty acid supplements in women at high risk for breast cancer
Authors: Straka Shana , Lester Joanne L. , Puchala Sarah , Rose Angela , Cole Rachel , Andridge Rebecca R. , Clinton Steven K. , Belury Martha A. , Yee Lisa D.
Published: October 2015

Background: The type of fat consumed in the diet may influence mammary tissue biology and breast cancer risk, with preclinical evidence for inhibitory effects of n-3 versus n-6 polyunsaturated fatty acids (PUFAs) on mammary carcinogenesis. Fish consumption and fish oil supplements are two strategies to increase dietary n-3 fatty acids.

Objective: To determine the effects of increased fish consumption on breast adipose tissue fatty acids, we conducted a study of dietary fish versus an n-3 fatty acid supplement in women at increased risk for developing breast cancer.

Design: In this three month randomized study, women at high risk for breast cancer received either (a) dietary fish in the form of canned salmon and albacore tuna at a dose of four 6 ounce servings/week or (b) two n-3 fatty acid capsules (1.68 g EPA+DHA)/day for three months. Subjects underwent fasting blood draws monthly and breast adipose tissue samples at baseline and three months for fatty acid profiling by gas chromatography.

Results: Both study interventions of dietary fish and n-3 PUFA capsule yielded increased EPA and DHA content in plasma (p<0.0001), erythrocyte membranes (p<0.0001), and breast adipose tissue samples (p <0.01) at 3 months, with also significantly increased total ω-3 PUFAs and decreased n-3/n-6 ratios (p<0.0001). Women taking n-3 PUFA capsules had a greater rise in plasma and erythrocyte membrane EPA relative to those consuming fish (p=0.002), without significant differences in DHA. BMI attenuated the incremental increase in EPA and DHA. Adherence was excellent in both groups at 93.9%, and higher in the dietary fish arm (p=0.01).

Conclusions: Dietary fish and n-3 PUFA capsules significantly increase breast adipose tissue EPA and DHA content and represent two well tolerated strategies for future clinical trials of dietary n-3 PUFAs for breast cancer prevention.

Citation Format: Shana Straka, Joanne L. Lester, Sarah Puchala, Angela Rose, Rachel Cole, Rebecca R. Andridge, Steven K. Clinton, Martha A. Belury, Lisa D. Yee. A pilot trial of dietary fish and ω-3 fatty acid supplements in women at high risk for breast cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B45.
Abstract B53: Predicting efficacy of chemopreventive agents in animal tumor assays by statistical modeling
Authors: Dunn Barbara K. , Steele Vernon E. , Fagerstrom Richard M. , Topp Carol F. , Ransohoff David , Ford Leslie G. , Kramer Barnett S.
Published: October 2015

NCI's Division of Cancer Prevention has over 25 years entered some 800 agents into a program designed to test cancer preventive efficacy. Early in the testing pathway are 2 sequential critical steps: (1) in vitro/in vivo morphologic assays and, (2) for agents successful in step 1, cancer-preventive testing (measured in terms of tumor incidence and multiplicity reduction) in animal tumor assays. The ultimate intention is to follow successful testing in animals with entry into clinical trial testing in humans. To facilitate the optimal selection of appropriate morphologic tests for specific disease-site animal tumor models, we undertook the current project. We evaluated the success of our strategy by determining how accurately the earlier stage (morphologic) assays predict efficacy in the later-stage (animal tumor) assays. Focusing on 210 agents that were tested in both morphologic and animal tumor assays, we carried out statistical modeling of how well the 6 most commonly used morphologic assays predicted drug efficacy in animal tumor models. Using multimodel inference, three statistical models were generated to evaluate the ability of these 6 morphologic assays to predict tumor outcomes in 3 different sets of animal tumor assays: (1) all tumor types, (2) breast cancer only, and (3) colon cancer only. Using this statistical modeling approach, each morphologic assay was assigned a value reflecting how strongly it predicted outcomes in each of the 3 different sets of animal tumor assays. The goal is to use predictive models such as these to guide our future decision-making with respect to selection of preventive agents as well as morphologic and animal tumor assays. In this manner, we hope to improve the efficiency of our overall approach to chemoprevention agent development.

Citation Format: Barbara K. Dunn, Vernon E. Steele, Richard M. Fagerstrom, Carol F. Topp, David Ransohoff, Leslie G. Ford, Barnett S. Kramer. Predicting efficacy of chemopreventive agents in animal tumor assays by statistical modeling. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B53.
Abstract CN01-02: Instrumenting the healthcare enterprise for discovery research
Authors: Murphy Shawn N.
Published: October 2015

It is critical for us to leverage healthcare technology to find ways to meet our goals in clinical research. The Informatics for Integrating Biology and the Bedside (i2b2) project is used to accrue patients for clinical trials using data from a hospital's medical record. It is also valuable as a platform for generally validating disease phenotypes as part of in-silico studies that explore associations of phenotypes with the information gathered from biologic samples such as the genotypes of the patients and their tissues. The software can adapt to Patient Surveys and Reported Outcomes as well as routine Electronic Medical Record data. The software can be used to support multisite trials across institutions using the Shared Healthcare Research Informatics Network (SHRINE).

Citation Format: Shawn N. Murphy. Instrumenting the healthcare enterprise for discovery research. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN01-02.
Abstract CN03-01: Dissemination and implementation of cancer prevention policies: The example of smoke-free public housing
Authors: Klassen Ann Carroll
Published: October 2015

Second and third hand smoke exposure increases risk for a number of cancers and other adverse health effects in smokers and non- smokers. Public health campaigns have reduced smoking in many types of public enclosed spaces, but the residential environment remains an important area for risk reduction. In multi-unit housing, significant exposure due to drift between units has led to market and policy efforts to promote smoke-free multi-unit housing options. Public housing authorities have implemented smoke-free policies in greater numbers since the 2009 HUD Healthy Homes Strategic Plan, but the implementation of smoke-free policies in public housing, which must serve diverse communities of low income families, disabled, and elderly residents, presents ethical and logistical challenges.

The Philadelphia Housing Authority is the fourth largest housing authority in the US, serving over 80,000 residents, and is among the largest to implement smoke-free policies. The Drexel School of Public Health, in partnership with the Philadelphia Department of Public Health and with funding from the Centers for Disease Control and Prevention, has conducted a longitudinal mixed methods evaluation of the implementation process.

Our formative evaluation began with in-depth interviews and focus groups with residents, including smokers and non-smokers, as well as PHA staff, policy leaders, and local tobacco control stakeholders, as well as ethnographic observations of the tobacco use culture in diverse housing communities in Philadelphia. We then conducted baseline interviews with a sample of residents in four communities, and conducted air nicotine monitoring in both residents' homes and in public areas, including elevators, laundry rooms, hallways, and lobbies. During implementation, we will continue to monitor resident knowledge, attitudes and tobacco related behaviors, as well as tobacco use in public and home environments.

Results will be discussed in the context of community behavior change, and tobacco control policies for high risk, low resource communities. As well, the Philadelphia example will be compared to other cities and communities, and to the broader theory of implementation science for public health.

Citation Format: Ann Carroll Klassen. Dissemination and implementation of cancer prevention policies: The example of smoke-free public housing. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN03-01.
Abstract CN10-01: Tumor surveillance strategies in pediatric hereditary cancer predisposition syndromes
Authors: Malkin David , Villani Anita , Wasserman Jonathan
Published: October 2015

Cancer is the most common cause of disease-related death in children beyond the neonatal period. Primary prevention has not been commonly considered in the management of childhood cancers as ‘environmental’ agents have not generally been associated with cancer risk. Evidence from genetic and genomic studies supports a rapidly increasing role for inherited or de novo genetic alterations in the etiology of many childhood cancers. Diverse phenotypes have been associated with many of these gene alterations, and genotype:phenotype correlations continue to be defined. Some cancer predisposition syndromes are associated with other non-neoplastic congenital or developmental anomalies, whereas other syndromes appear to be limited to occurrence of a few or many possible cancer types. In the past, the role of genetic testing of children was questioned based on the lack of evidence for effective intervention or improved outcomes. However, the creation and implementation of several comprehensive multi-modality surveillance protocols has offered means by which children at genetic risk of cancer may benefit from early tumor detection and treatment to reduce morbidity and mortality. Emerging discussion of potential opportunities for targeted chemoprevention have also begun. This talk will highlight some of these scenarios, present algorithms whereby such approaches can be used, and explore the complex medical, psychosocial, ethical and financial challenges and opportunities whereby biological/genetic understanding of childhood cancer risk, coupled with effective clinical surveillance can beneficially alter the natural course of hereditary cancer in children.

Citation Format: David Malkin, Anita Villani, Jonathan Wasserman. Tumor surveillance strategies in pediatric hereditary cancer predisposition syndromes. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN10-01.
Abstract CN11-03: SIRT3 is a mitochrondial tumor suppressor in breast cancer
Authors: Gius David
Published: October 2015

It is a well-established scientific observation that mammalian cells contain fidelity or watchdog proteins that maintain the correct function of cellular organelles. Over the past several years, the Sirtuin deacetylase family protein Sirt3 has emerged as a mitochondrial fidelity protein that directs energy generation and regulates reactive oxygen species (ROS) scavenging proteins. Genetic deletion of these fidelity proteins has been shown to create a cellular environment that is permissive for the development of cellular damage associated with processes such as aging and breast ductal cell carcinogenesis. In this regard, we have previously shown that mice lacking the mitochondrial Sirtuin-3 (Sirt3) gene develop estrogen receptor (ER+) positive, p53 wild-type, poorly differentiated invasive ductal carcinomas (IDC) (Kim et al., 2010, Cancer Cell), a subtype of malignancy similar to luminal B breast cancer that is predominantly observed in older women. Mice lacking Sirt3 also exhibit increased ROS, including superoxide due to the aberrant acetylation of manganese superoxide dismutase (MnSOD) resulting in decreased enzymatic ROS scavenging activity. In addition, over expressing a mutant deacetylated-mimic MnSOD isoform, which exhibits increased SOD enzymatic activity, reversed the tumor permissive phenotype (Tao et al, 2010, Molecular Cell) observed in breast tumor cells lacking Sirt3.

Finally, in collaboration with Dr. Joe Bass (Corresponding Author, Northwestern University) a link between SIRT3 and the clock proteins, in the form of mitochondrial NAD+ concentrations has been discovered. Specifically, a clock protein loop directs SIRT3, via NAD+ bioavailability, to regulate mitochondrial glycolytic and oxidative metabolism, as well as MnSOD lysine acetylation and detoxification activity. Furthermore, NAD+ supplementation decreased MnSOD acetylation and significantly restored mitochondrial function in circadian mutant mice by a mechanism involving SIRT3 activity (Peek et al., 2013, Science). These results suggest that circadian clock proteins coordinate mitochondrial metabolism, in part via the modulation of protein acetylation, to synchronize metabolic and oxidative pathways with circadian rhythms.

Citation Format: David Gius. SIRT3 is a mitochrondial tumor suppressor in breast cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN11-03.
Abstract PL02-02: Tomatoes, lycopene, and prostate cancer
Authors: Clinton Steven K.
Published: October 2015

In 1995, the first large prospective cohort data emerged from the Health Professionals Follow-up Study (HPFS) demonstrating a protective association between the intake of tomatoes and processed tomato products and a lower risk of prostate cancer (PCa). By utilizing data-bases of food content of carotenoids it has been possible to demonstrate similar associations between the estimated intake of lycopene (LYC), the non-provitamin A carotenoid providing the familiar red color of tomatoes, and PCa risk. With an additional two decades of monitoring the associations originally identified in the HPFS remain consistent in the 2014 update, while other epidemiologic studies are less convincing. LYC and other carotenoids were documented in human prostate tissue supporting the hypothesis of a direct effect on prostate carcinogenesis. Studies employing various laboratory models from multiple investigators show that tomato components or pure LYC have a protective impact on experimental prostate carcinogenesis. Although an antioxidant mechanism is frequently imputed based upon the known capacity of LYC to quench reactive oxygen species, other potential mechanisms of action related to hormonal activity, cell signaling and growth control, angiogenesis, and metastasis have emerged. Yet, proof of a protective relationship remains elusive and there are many obstacles to defining the impact of specific plant derived phytochemicals for human prostate cancer risk. The importance of dose-response, host genetics, and the complexity of human prostate cancer are but a few of the challenges faced in establishing a causal relationship. The examination of a tomato, lycopene, and prostate cancer relationship provides an example for considering how we as a discipline will address the challenges of defining food or phytochemical based interventions for cancer risk.

Citation Format: Steven K. Clinton. Tomatoes, lycopene, and prostate cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL02-02.
Abstract PL03-03: ER stress and TNF signaling control the progression from simple steatosis to non-alcoholic steatohepatitis (NASH)
Authors: Karin Michael
Published: October 2015

In addition to insulin resistance and type II diabetes, the obesity epidemic had resulted in a large increase in the incidence of non-alcoholic fatty liver disease (NAFLD), which ranges in its manifestations from simple steatosis without liver inflammation and fibrosis to NASH, which is accompanied by liver damage and fibrosis. The mechanisms that govern the progression from simple steatosis to NASH are obscure, but are thought to depend on secondary risk factors that act together with obesity. To study these mechanisms we have developed a new mouse model of NASH which closely mimics all of the features of human NASH. This model is based on the feeding of MUP-uPA mice, which specifically express urokinase plasminogen activator (uPA) in their hepatocytes. Unlike wild type mice, which only develop simple steatosis and insulin resistance after feeding with high fat diet (HFD), MUP-uPA mice on HFD exhibit pronounced liver damage, inflammation, fibrosis and all the classical signs of NASH. The key factors that drive NASH pathogenesis in MUP-uPA mice on HFD are ER stress and excessive TNF production. Interestingly, activation of type I TNF receptor (TNFR1) also controls lipogenesis and steatosis in MUP-uPA mice. Both ER stress and TNFR1 signaling appear to be suitable therapeutic targets for the prevention of NASH and inhibition of its progression to steatotic hepatocellular carcinoma.

Citation Format: Michael Karin. ER stress and TNF signaling control the progression from simple steatosis to non-alcoholic steatohepatitis (NASH). [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL03-03.
Abstract PL04-02: ATM: Bridging DNA damage responses and metabolic regulation
Authors: Kastan Michael B. , Valentin-Vega Yasmine , Brown Adam , Scarbrough Peter , Fleenor Donald
Published: October 2015

Much of our understanding of the mechanisms involved in cellular DNA damage response pathways have come from studies of human cancer susceptibility syndromes. ATM, the gene mutated in the cancer-prone, radiosensitive disorder, Ataxia-telangiectasia (A-T), is a protein kinase that is a central mediator of responses to DNA double strand breaks in cells. Once activated, ATM phosphorylates numerous substrates in the cell that modulate the cell's response to the DNA damage. p53, one of the many targets of the ATM kinase, is a critical mediator of cell cycle changes and cell death signaling following DNA damage and other stresses. Though ATM clearly plays a central role in mediating cellular responses to DNA breakage, some of the clinical abnormalities in A-T are difficult to attribute directly to alterations in DNA damage signaling. The broad-based symptoms in A-T and recently acquired data suggest that ATM has physiologic roles that extend beyond its regulation of DNA damage responses. In particular, ATM appears to affect insulin signaling pathways and to have a direct role in regulating mitochondrial function. Interestingly, we found in mouse models of A-T that these mitochondrial defects associated with ATM deficiency appear to be a contributing factor to cancer development in A-T. These new insights suggest that Ataxia-Telangiectasia should be considered, at least in part, as a mitochondrial dysfunction disease and provide links between cancer-related DNA damage signaling, general metabolic signaling pathways, and cancer development.

Citation Format: Michael B. Kastan, Yasmine Valentin-Vega, Adam Brown, Peter Scarbrough, Donald Fleenor. ATM: Bridging DNA damage responses and metabolic regulation. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL04-02.
Abstract PL04-03: Evidence for increased muscle breakdown associated with early pancreatic cancer
Authors: Heiden Matthew G. Vander
Published: October 2015

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression had not been studied. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We found that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. Utilizing genetically engineered mouse models of PDAC, we have confirmed that these elevations represent a marker of early, sub-clinical disease. Furthermore, using these model systems, we demonstrate that the increase in plasma BCAAs reflects a breakdown of tissue protein that accompanies early stage disease. Together, these findings suggest that altered whole body amino acid metabolism is an early event in development of PDAC, and that elevations in BCAAs can be seen in patients years before their pancreatic cancer diagnosis.

Citation Format: Matthew G. Vander Heiden. Evidence for increased muscle breakdown associated with early pancreatic cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL04-03.
Abstract PL06-02: The clock in the cell
Authors: Merrow Martha
Published: October 2015

The circadian clock is an endogenous, cell-based timing mechanism. It has apparently evolved as a response to the highly predictable and metabolically challenging light/dark cycle. Circadian clocks are characterized as having a free running, circa 24h rhythm in constant conditions, an entrainment mechanism whereby those rhythms become exactly 24h, robustness, precision and compensation towards environmental variability such as temperature. While most of our knowledge concerning molecular mechanisms of the daily clock comes from the free running state, the clock is always found in the entrained state in nature. It is this process, the biological oscillator finds its unique phase relationship with the environmental cycle, that leading to temporal compartmentation of various functions and activities. The clock controls gene expression, metabolism, physiology and complex behaviors by organizing them to specific times of day. Working ‘against the clock’ (e.g. in shift work) has been associated with increased incidence of cancers. I will review the molecular and genetic mechanisms that might be involved in this process.

Citation Format: Martha Merrow. The clock in the cell. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL06-02.
Abstract PR07: Calorie restriction normalizes global microRNA expression by preventing the loss of Dicer expression during mammary tumorigenesis
Authors: Devlin Kaylyn L. , Sanford Tiffany , Mambo Elizabeth , Hursting Stephen D.
Published: October 2015

MicroRNA (miRNAs) are small, post-transcriptional regulators that play an integral role in maintenance of cellular functions and whose dyregulation has been shown to promote many types of cancer, including breast cancer. Global downregulation of miRNAs has emerged as a common theme in human breast tumors and has been shown to contribute to oncogenesis. One of the primary mechanisms through which miRNAs are globally dysregulated is downregulation of enzymes involved in miRNA biogenesis. We aim to establish how calorie restriction (CR), which potently inhibits breast cancer progression, regulates global miRNA expression and miRNA biogenesis enzyme functionality in mammary tumors. To address these questions, 100 female Sprague Dawley rats were administered either dimethylbenz(a)anthracene (DMBA) or vehicle control at 50 days of age, then randomized to receive either control (AIN-76A) diet ad-libitum (n=40) or a 30% CR diet regiment (n=60). Resultant mammary tumors were allowed to develop for 12 weeks. Calorie restriction significantly increased survival to study endpoint relative to control diet (75% vs 35%, respectively) (p=0.0047). Furthermore, of the animals that developed tumors, CR significantly decreased median tumor area by 56% compared to control diet (109.4 mm2 vs 250.9 mm2, respectively) (p=0.0286). Global miRNA expression was analyzed through miRNA-specific sequencing. Calorie restriction had a broad effect on miRNA expression, illustrated by the fact that of all the miRNAs with a greater than two-fold expression difference between CR and control, 80% are overexpressed in CR tumors compared to control tumors. These results can be explained by the additional finding that CR was able to prevent the loss of Dicer expression, a key miRNA biogenesis enzyme, observed in control-fed mammary tumor tissue compared to normal tissue. This important finding suggests that global miRNA normalization through the retention of Dicer expression during cancer progression could be a contributing mechanism to CR's anticancer effects. We plan to further these investigations by exogenously manipulating Dicer expression in Rama25 cells, which were originally derived from a DMBA-induced mammary tumor from a Sprague Dawley rat, and analyzing the resultant tumorigenic potential in vitro and in vivo. The results obtained will provide insights into the mechanisms of breast cancer progression and how CR inhibits progression through microRNA modulation.

Citation Format: Kaylyn L. Devlin, Tiffany Sanford, Elizabeth Mambo, Stephen D. Hursting. Calorie restriction normalizes global microRNA expression by preventing the loss of Dicer expression during mammary tumorigenesis. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PR07.
Abstract PR12: Adolescent inflammation and body mass index in relation to colorectal cancer risk
Authors: Kantor Elizabeth D. , Udumyan Ruzan , Signorello Lisa B. , Giovannucci Edward L. , Montgomery Scott , Fall Katja
Published: October 2015

Inflammation and obesity in adulthood have been associated with risk of colorectal cancer (CRC); however, less is known about the role of early-life inflammation and body mass index (BMI) in relation to CRC risk. We therefore sought to evaluate these associations in a cohort of 239,464 Swedish men compulsorily enlisted in the military in late adolescence (ages 16-20 years). At the time of the conscription assessment (1969-1976), erythrocyte sedimentation rate (ESR) was assayed as a measure of inflammation and height and weight were measured. The conscription registry has been linked with national cancer and mortality registries, and men have been followed for CRC through January 1, 2010. Over an average of 35 years of follow-up, 885 cases of CRC occurred, including 501 colon cancers and 384 rectal cancers. Cox regression was used to estimate Hazard Ratios (HRs) and corresponding 95% Confidence Intervals (95% CIs) adjusted for covariates, including childhood socioeconomic status. Men with high inflammation (ESR ≥ 15 mm/hr) in late adolescence had 63% higher risk of CRC (HR: 1.63; 95% CI: 1.08, 2.46) than men with low inflammation (ESR <10 mm/hr) (p-trend: 0.006). This association did not significantly differ by anatomic site (p-difference: 0.50), though the trend was statistically significant for cancers of the colon only (p-trend: 0.009). Late-adolescent BMI was also significantly associated with CRC risk (p-trend: <0.001), with obese adolescents (BMI ≥ 30 kg/m2) experiencing a 2.37-fold higher risk of CRC (HR: 2.37; 95% CI: 1.50, 3.74) than their normal weight counterparts (BMI 18.5-<25 kg/m2). Again, the association between BMI and cancer risk did not significantly vary by anatomic site (p-difference: 0.40), although the trend was statistically significant for cancers of the colon only (p-trend: < 0.001). These analyses were mutually adjusted for BMI and ESR, suggesting that both adolescent inflammation and BMI may be independently associated with CRC risk. Future research is needed to better understand how life-course inflammation and BMI relate to colorectal cancer.

Citation Format: Elizabeth D. Kantor, Ruzan Udumyan, Lisa B. Signorello, Edward L. Giovannucci, Scott Montgomery, Katja Fall. Adolescent inflammation and body mass index in relation to colorectal cancer risk. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PR12.
Innate Lymphoid Cells in Cancer
Authors: Vallentin Blandine , Barlogis Vincent , Piperoglou Christelle , Cypowyj Sophie , Zucchini Nicolas , Chéné Matthieu , Navarro Florent , Farnarier Catherine , Vivier Eric , Vély Frédéric
Published: October 2015

The world of lymphocytes has recently expanded. A group of cells, innate lymphoid cells (ILC), has been defined. It includes lymphoid cells that have been known for decades, such as natural killer (NK) cells and lymphoid tissue–inducer (LTi) cells. NK cells recognize a vast array of tumor cells, which they help to eliminate through cytotoxicity and the production of cytokines, such as IFNγ. Advances in our understanding of NK-cell biology have led to a growing interest in the clinical manipulation of these cells in cancer. The other ILCs are found mostly in the mucosae and mucosal-associated lymphoid tissues, where they rapidly initiate immune responses to pathogens without the need for specific sensitization. Here, we outline the basic features of ILCs and review the role of ILCs other than NK cells in cancer. Much of the role of these ILCs in cancer remains unknown, but several findings should lead to further efforts to dissect the contribution of different ILC subsets to the promotion, maintenance, or elimination of tumors at various anatomic sites. This will require the development of standardized reagents and protocols for monitoring the presence and function of ILCs in human blood and tissue samples. Cancer Immunol Res; 3(10); 1109–14. ©2015 AACR.
Retinal Involvement in a Patient with Cerebral Manifestation of Chronic Graft-Versus-Host-Disease
Authors: Blecha Christiane , Angstwurm Klemens , Wolff Daniel , Holler Ernst , Helbig Horst , Grassinger Jochen , Rennert Janine , Kleiter Ingo , Huber Elisabeth , Schmid Christoph , Dietrich-Ntoukas Tina
Published: October 2015

Background: We report a 35-year-old female patient with cerebral manifestations of chronic graft-versus-host disease (cGvHD) and putative retinal involvement after allogeneic peripheral blood stem cell transplantation (alloHSCT). Patient and Methods: The patient experienced recurrent episodes of fever and encephalitic signs 7 months after alloHSCT during taper of immunosuppression (IS). Results: Cerebral magnetic resonance imaging (MRI) showed non-gadolinium-enhancing confluent periventricular lesions and cerebrospinal fluid inflammation. After exclusion of infectious causes, treatment with steroids and antiepileptics improved cognitive deficits. Steroid reduction provoked a relapse responding to IS. 2 years later, she complained of right-sided blurred vision and floaters; both eyes showed whitish circumscribed retinal infiltrations, cellular infiltration of the vitreous and mild bilateral optic disc edema. Oncological and neurological work-up ruled out infectious diseases and other GvHD manifestations. Symptoms and signs resolved under continued systemic IS, leaving pigmented retinal scars. After IS withdrawal, classical cutaneous cGvHD developed, resolving on systemic IS. 94 months after transplantation, she is doing well. Conclusion: To our knowledge, this is the first observation of retinal involvement of cerebral cGvHD manifestations with retinal infiltrations documented in the absence of other causes and in parallel to periventricular lesions in cerebral MRI. Based on bone marrow histology, we discuss a small vessel pathophysiology of cGvHD.
Implementation of NAT Screening for West Nile Virus and Experience with Seasonal Testing in Germany
Authors: Dreier Jens , Vollmer Tanja , Hinse Dennis , Heuser Ernst Joachim , Pisani Giulio , Knabbe Cornelius
Published: October 2015

Background: West Nile virus (WNV) can be transmitted by transfusion through infected blood components. In Germany, a 28-day deferral for blood donors of therapeutic blood components who had spent at least 2 days in WNV-endemic areas from June 1 to November 30, 2014 was enforced. Otherwise, screening of blood donors for WNV RNA or the application of pathogen reduction techniques are appropriate alternatives. Methods: In the present study, we evaluated NAT screening for the detection of WNV in blood components. A total of 58 minipools consisting of 357 individual blood donors were screened for the presence of WNV RNA employing an automated high-volume extraction method using the RealStar WNV RT-PCR Kit. Additionally, different WNV reference reagents were quantified to prove the status quo of standardization. Four different WNV real-time NAT kits were compared using samples of an external quality assessment panel. Results: The 95% lower detection limit of the WNV MP-NAT was determined to 30.2 copies/ml (95% CI 24.2-45.4 copies/ml). No WNV RNA-positive minipool was detected. Quantification of WNV reference reagents revealed shortcomings in standardization. Comparison of several WNV NAT assays showed considerable differences in assay sensitivities and particularly a missing detection of WNV lineage 2. Implementation of seasonal WNV MP-NAT screening was demonstrated. Conclusion: Actually, WNV infections in Germany are rare events introduced by returning travelers, but surveillance of these emerging infections is important for safety in blood supply. The validation study pointed out the need for standardization of WNV NAT because of current lack of an international standard for WNV RNA.
Is Cryotherapy Friend or Foe for Symptomatic Cervical Ectopy?
Authors: Çekmez Yasemin , Şanlıkan Fatih , Göçmen Ahmet , Vural Aylin , Türkmen Simge Bağcı
Published: October 2015

Objective: To evaluate the success rates and clinical outcomes of cervical cryotherapy applied to cervical ectopy for symptomatic relief. Subjects and Methods: A total of 124 women who underwent cryotherapy for symptomatic treatment of cervical ectopy were included in this study. Indications for treatment were: abundant leucorrhoea (n = 114), post-coital bleeding (n = 22), recurrent cervicitis (n = 30) and pelvic pain (n = 12). Cryotherapy consisted of the use of carbon dioxide at -89°C to destroy the ectopic columnar epithelium by freezing, and it was transmitted to the ectopy through a flat cryoprobe. No routine anaesthesia or analgesia was administered. All patients were questioned about the status of their symptoms after 6 weeks of treatment. Results: The highest success rate was obtained in patients with abundant leucorrhoea (n = 102; 89.5%), while the lowest success rate was achieved in subjects with pelvic pain (n = 7; 58%). After treatment, no severe complications were observed, except for hydrorrhoea for a few days. Success rates were 9 times lower in patients who had 3 or more cervicitis episodes per 6 months. Conclusion: In this study, the success rate of cryotherapy was highest in patients with abundant leucorrhoea and lowest in patients with pelvic pain and recurrent cervicitis. Hence, we recommend that clinicians perform the procedure in such patients without much delay.