Publications by authors named "Ernest T Hawk"

83 Publications

Gut Microbiome Features Associated with Liver Fibrosis in Hispanics, a Population at High Risk for Fatty Liver Disease.

Hepatology 2021 Oct 11. Epub 2021 Oct 11.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background And Aims: Hispanics are disproportionately affected by non-alcoholic fatty liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Preventive strategies and non-invasive means to identify those in this population at high risk for liver fibrosis, are urgently needed. We aimed to characterize the gut microbiome signatures and related biological functions associated with liver fibrosis in Hispanics and identify environmental and genetic factors affecting them.

Approach And Results: Subjects of the population-based Cameron County Hispanic Cohort (n=217) were screened by vibration-controlled transient elastography (FibroScan). Among them, 144 (66.7%) had steatosis and 28 (13.0%) had liver fibrosis. The gut microbiome of subjects with liver fibrosis was enriched with immunogenic commensals (e.g. Prevotella copri, Holdemanella, Clostridiaceae 1) and depleted of Bacteroides caccae, Parabacteroides distasonis, Enterobacter and Marinifilaceae. The liver fibrosis-associated metagenome was characterized by changes in the urea cycle, L-citrulline biosynthesis and creatinine degradation pathways, and altered synthesis of B vitamins and lipoic acid. These metagenomic changes strongly correlated with the depletion of Parabacteroides distasonis and enrichment of Prevotella and Holdemanella. Liver fibrosis was also associated with depletion of bacterial pathways related to L-fucose biosynthesis. Alcohol consumption, even moderate, was associated with high Prevotella abundance. The single nucleotide polymorphisms rs3769502 and rs7573751 in the NCK2 gene positively associated with high Prevotella abundance.

Conclusion: Hispanics with liver fibrosis display microbiome profiles and associated functional changes that may promote oxidative stress and a pro-inflammatory environment. These microbiome signatures, together with NCK2 polymorphisms, may have utility in risk modeling and disease prevention in this high-risk population.
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http://dx.doi.org/10.1002/hep.32197DOI Listing
October 2021

Circulating Fatty Acids Associated with Advanced Liver Fibrosis and Hepatocellular Carcinoma in South Texas Hispanics.

Cancer Epidemiol Biomarkers Prev 2021 Sep 21;30(9):1643-1651. Epub 2021 Jun 21.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Hispanics in South Texas have high rates of hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Liver fibrosis severity is the strongest predictive factor of NAFLD progression to HCC. We examined the association between free fatty acids (FA) and advanced liver fibrosis or HCC in this population.

Methods: We quantified 45 FAs in plasma of 116 subjects of the Cameron County Hispanic Cohort, 15 Hispanics with HCC, and 56 first/second-degree relatives of Hispanics with HCC. Liver fibrosis was assessed by FibroScan.

Results: Advanced liver fibrosis was significantly associated with low expression of very long chain (VLC) saturated FAs (SFA), odd chain SFAs, and VLC n-3 polyunsaturated FAs [PUFA; AOR; 95% confidence interval (CI), 10.4 (3.7-29.6); < 0.001; 5.7 (2.2-15.2); < 0.001; and 3.7 (1.5-9.3); = 0.005]. VLC n3-PUFAs significantly improved the performance of the noninvasive markers for advanced fibrosis - APRI, FIB-4, and NFS. Plasma concentrations of VLC SFAs and VLC n-3 PUFAs were further reduced in patients with HCC. Low concentrations of these FAs were also observed in relatives of patients with HCC and in subjects with the rs738409 homozygous genotype.

Conclusions: Low plasma concentrations of VLC n-3 PUFAs and VLC SFAs were strongly associated with advanced liver fibrosis and HCC in this population. Genetic factors were associated with low concentrations of these FAs as well.

Impact: These results have implications in identifying those at risk for liver fibrosis progression to HCC and in screening this population for advanced fibrosis. They also prompt the evaluation of VLC n-3 PUFA or VLC SFA supplementation to prevent cirrhosis and HCC.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419070PMC
September 2021

The Performance of Colorectal Cancer Screening in Brazil: The First Two Years of the Implementation Program in Barretos Cancer Hospital.

Cancer Prev Res (Phila) 2021 02 30;14(2):241-252. Epub 2020 Sep 30.

Department of Prevention, Barretos Cancer Hospital, Barretos, Brazil.

Colorectal cancer is the second most common cancer in Brazil. Yet, a nationally organized colorectal screening program is not implemented. Barretos Cancer Hospital (BCH) is one of the largest Brazilian institution that cares for underserved patients. BCH developed a fecal immunochemical test (FIT)-based organized colorectal cancer screening program to improve colorectal cancer outcomes.This study aims to present the quality/performance measures of the first 2 years of the FIT-based colorectal cancer screening program and its impact on the colorectal cancer disease stage. Between 2015 and 2017, a total of 6,737 individuals attending the Outpatient Department of Prevention or the Mobile Unit of BCH, which visits 18 cities of Barretos county, ages 50 to 65 years, were personally invited by a health agent/nurse practitioner. Exclusion criteria were personal history of colorectal cancer, adenomatous polyps, inflammatory bowel disease, and colonoscopy, or flexible sigmoidoscopy performed in the past 5 years. European Union (EU) guidelines for colorectal cancer screening programs were evaluated. Overall, 92.8% returned the FIT, with an inadequate examination rate of 1.5%. Among the 6,253 adequately tested, 12.5% had a positive result. The colonoscopy compliance and completion rates were 84.6 and 98.2%, respectively. The PPVs were 60.0%, 16.5%, and 5.6% for adenoma, advanced adenoma, and cancer, respectively. Stage distribution of screen-detected cancers shows earlier stages than clinically diagnosed colorectal cancer cancers reported at BCH and Brazilian cancer registries. Our colorectal cancer screening program achieved desirable quality metrics, aligned with the EU guidelines. The observed shift toward earlier colorectal cancer stages suggests an exciting opportunity to improve colorectal cancer-related cancers in Brazil.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0179DOI Listing
February 2021

The ASPREE Trial: An Unanticipated Stimulus for Greater Precision in Prevention?

J Natl Cancer Inst 2021 03;113(3):221-222

Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1093/jnci/djaa115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936052PMC
March 2021

Strategies to identify hepatitis C virus infection in patients receiving anticancer therapy: a cross-sectional study.

Support Care Cancer 2021 Jan 20;29(1):97-105. Epub 2020 Apr 20.

Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Optimal hepatitis C virus (HCV) screening strategies for cancer patients have not been established. We compared the performance of selective HCV screening strategies.

Methods: We surveyed patients presenting for first systemic anticancer therapy during 2013-2014 for HCV risk factors. We estimated the prevalence of positivity for HCV antibody (anti-HCV) and examined factors associated with anti-HCV status using Fisher's exact test or Student's t test. Sensitivity was calculated for screening patients born during 1945-1965, patients with ≥ 1 other risk factor, or both cohorts ("combined screening").

Results: We enrolled 2122 participants. Median age was 59 years (range, 18-91); 1138 participants were women. Race/ethnicity distribution was white non-Hispanic, 76% (n = 1616); Hispanic, 11% (n = 233); black non-Hispanic, 8% (n = 160); Asian, 4% (n = 78); and other, 2% (n = 35). Primary cancer distribution was non-liver solid tumor, 78% (n = 1664); hematologic cancer, 20% (n = 422); and liver cancer, 1% (n = 28). Prevalence of anti-HCV was 1.93% (95% CI, 1.39%-2.61%). Over 28% of patients with detectable HCV RNA were unaware of infection. Factors significantly associated with anti-HCV positivity included less than a bachelor's degree, birth in 1945-1965, chronic liver disease, injection drug use, and blood transfusion or organ transplant before 1992. A total of 1315 participants (62%), including 39 of 41 with anti-HCV, reported ≥ 1 risk factor. Sensitivity was 80% (95% CI, 65-91%) for birth-cohort-based, 68% (95% CI, 52-82%) for other-risk-factor-based, and 95% (95% 83-99%) for combined screening.

Conclusion: Combined screening still missed 5% of patients with anti-HCV. These findings favor universal HCV screening to identify all HCV-infected cancer patients.
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http://dx.doi.org/10.1007/s00520-020-05456-3DOI Listing
January 2021

E-Cigarettes: Unstandardized, Under-Regulated, Understudied, and Unknown Health and Cancer Risks.

Cancer Res 2019 12 28;79(24):6079-6083. Epub 2019 Oct 28.

Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.

E-cigarettes have the ability to deliver nicotine in a manner that is similar to, and, theoretically, safer than, combusted tobacco. However, these devices are extremely heterogeneous and regulation has struggled to keep up with their rapid evolution. A compilation of early data suggest that e-cigarettes may contain numerous toxic substances, including known carcinogens. However, there are few data available on the short- and long-term health effects of e-cigarettes, including any potential effect on cancer risk. Until more is known, e-cigarettes should not be considered a safe alternative to combusted tobacco use.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911629PMC
December 2019

Functional characterization of variants identified in familial adenomatous polyposis adenomas.

Oncotarget 2019 Jun 11;10(39):3939-3951. Epub 2019 Jun 11.

Functional and Chemical Genomics, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Germline mutations in the tumor suppressor () define Familial Adenomatous Polyposis (FAP), the genetic predisposition to developing adenomatous polyps. Recent sequencing of FAP adenomas have challenged established dogma that mutations alone represent the adenoma mutational landscape because recurrent somatic mutations in non-WNT pathway genes were also discovered. In particular, one of these novel genes, , presented E20K and E70K mutations that are predicted to be deleterious . We utilized zebrafish embryos to determine if these mutations affect function and perform novel biology in an APC-dependent pathway . Human () and mRNA injection rescued zebrafish knockdown lordosis phenotype while did not. In the FAP zebrafish model, we show that , but not retinoic acid, regulates expression. Injection of and , but not , to homozygous zebrafish initiated gut differentiation while knockdown in wildtype embryos led to decreased intestinal development and differentiation. Finally, targeted sequencing of 37 additional FAP adenomas revealed mutations in 20% of these samples. Overall, our work supports a mechanism where regulates and that overall perturbation could work in concert with germline mutations in advancing adenomas to a more transformed state prior to progression to adenocarcinoma.
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http://dx.doi.org/10.18632/oncotarget.27003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570471PMC
June 2019

Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lung.

EBioMedicine 2019 Apr 21;42:296-303. Epub 2019 Mar 21.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Genomic investigation of atypical adenomatous hyperplasia (AAH), the only known precursor lesion to lung adenocarcinomas (LUAD), presents challenges due to the low mutant cell fractions. This necessitates sensitive methods for detection of chromosomal aberrations to better study the role of critical alterations in early lung cancer pathogenesis and the progression from AAH to LUAD.

Methods: We applied a sensitive haplotype-based statistical technique to detect chromosomal alterations leading to allelic imbalance (AI) from genotype array profiling of 48 matched normal lung parenchyma, AAH and tumor tissues from 16 stage-I LUAD patients. To gain insights into shared developmental trajectories among tissues, we performed phylogenetic analyses and integrated our results with point mutation data, highlighting significantly-mutated driver genes in LUAD pathogenesis.

Findings: AI was detected in nine AAHs (56%). Six cases exhibited recurrent loss of 17p. AI and the enrichment of 17p events were predominantly identified in patients with smoking history. Among the nine AAH tissues with detected AI, seven exhibited evidence for shared chromosomal aberrations with matched LUAD specimens, including losses harboring tumor suppressors on 17p, 8p, 9p, 9q, 19p, and gains encompassing oncogenes on 8q, 12p and 1q.

Interpretation: Chromosomal aberrations, particularly 17p loss, appear to play critical roles early in AAH pathogenesis. Genomic instability in AAH, as well as truncal chromosomal aberrations shared with LUAD, provide evidence for mutation accumulation and are suggestive of a cancerized field contributing to the clonal selection and expansion of these premalignant lesions. FUND: Supported in part by Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150079 (PS and HK), NIH grant R01HG005859 (PS) and The University of Texas MD Anderson Cancer Center Core Support Grant.
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http://dx.doi.org/10.1016/j.ebiom.2019.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491940PMC
April 2019

Real-Time Interrogation of Aspirin Reactivity, Biochemistry, and Biodistribution by Hyperpolarized Magnetic Resonance Spectroscopy.

Angew Chem Int Ed Engl 2019 03 20;58(13):4179-4183. Epub 2019 Feb 20.

Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.

Hyperpolarized magnetic resonance spectroscopy enables quantitative, non-radioactive, real-time measurement of imaging probe biodistribution and metabolism in vivo. Here, we investigate and report on the development and characterization of hyperpolarized acetylsalicylic acid (aspirin) and its use as a nuclear magnetic resonance (NMR) probe. Aspirin derivatives were synthesized with single- and double- C labels and hyperpolarized by dynamic nuclear polarization with 4.7 % and 3 % polarization, respectively. The longitudinal relaxation constants (T ) for the labeled acetyl and carboxyl carbonyls were approximately 30 seconds, supporting in vivo imaging and spectroscopy applications. In vitro hydrolysis, transacetylation, and albumin binding of hyperpolarized aspirin were readily monitored in real time by C-NMR spectroscopy. Hyperpolarized, double-labeled aspirin was well tolerated in mice and could be observed by both C-MR imaging and C-NMR spectroscopy in vivo.
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http://dx.doi.org/10.1002/anie.201812759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467058PMC
March 2019

AACR White Paper: Shaping the Future of Cancer Prevention - A Roadmap for Advancing Science and Public Health.

Cancer Prev Res (Phila) 2018 12;11(12):735-778

Division of Cancer Prevention & Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX.

The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling-from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1β, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold "Cancer Interception" initiative.
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http://dx.doi.org/10.1158/1940-6207.CAPR-18-0421DOI Listing
December 2018

Perspectives on Strengthening Cancer Research and Control in Latin America Through Partnerships and Diplomacy: Experience of the National Cancer Institute's Center for Global Health.

J Glob Oncol 2018 09;4:1-11

Silvina Frech, Catherine A. Muha, Lisa M. Stevens, Edward L. Trimble, Roxanne Brew, Doug Puricelli Perin, Paul C. Pearlman, and Brenda Kostelecky, National Cancer Institute, Rockville, MD; Silvana Luciani, Pan American Health Organization; Cristina Rabadan-Diehl, US Department of Health and Human Services; Denise Duran, Centers for Disease Control and Prevention, Washington, DC; Alejandro Mohar, Instituto Nacional de Cancerología, Mexico City, Mexico; Marion Piñeros, International Agency for Research on Cancer, Lyon, France; Tatiana Vidaurre, Instituto Nacional de Enfermedades Neoplásicas, Surquillo, Peru; Douglas R. Morgan, Vanderbilt-Ingram Cancer Center, Nashville, TN; Ernest T. Hawk, Kathleen M. Schmeler, Lewis E. Foxhall, and Melissa S. Lopez, The University of Texas MD Anderson Cancer Center, Houston, TX; Melissa Rendler-Garcia, Union for International Cancer Control, Geneva, Switzerland; Eduardo L. Cazap, Sociedad Latinoamericana y del Caribe del Oncología Médica, Buenos Aires, Argentina; Luiz Santini and Walter Zoss, Red de Institutos e Instituciones Nacionales de Cáncer, Sao Paolo, Brazil; Lucia B. Delgado, Universidad de la República, Montevideo, Uruguay; and Leslie Given and Karin Hohman, Strategic Health Concepts, Arvada, CO.

According to the Pan American Health Organization, noncommunicable diseases, including cancer, are the leading causes of preventable and premature death in the Americas. Governments and health care systems in Latin America face numerous challenges as a result of increasing morbidity and mortality from cancer. Multiple international organizations have recognized the need for collaborative action on and technical support for cancer research and control in Latin America. The Center for Global Health at the US National Cancer Institute (NCI-CGH) is one entity among many that are working in the region and has sought to develop a strategy for working in Latin America that draws on and expands the collaborative potential of engaged, skilled, and diverse partners. NCI-CGH has worked toward developing and implementing initiatives in collaboration with global partners that share the common objectives of building a global cancer research community and translating research results into evidence-informed policy and practice. Both objectives are complementary and synergistic and are additionally supported by an overarching strategic framework that is focused on partnerships and science diplomacy. This work highlights the overall strategy for NCI-CGH engagement in Latin America through partnerships and diplomacy, and highlights selected collaborative efforts that are aimed at improving cancer outcomes in the region.
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http://dx.doi.org/10.1200/JGO.17.00149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223440PMC
September 2018

Bioactive lipid metabolism in platelet "first responder" and cancer biology.

Cancer Metastasis Rev 2018 09;37(2-3):439-454

Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA.

Platelets can serve as "first responders" in cancer and metastasis. This is partly due to bioactive lipid metabolism that drives both platelet and cancer biology. The two primary eicosanoid metabolites that maintain platelet rapid response homeostasis are prostacyclin made by endothelial cells that inhibits platelet function, which is counterbalanced by thromboxane produced by platelets during activation, aggregation, and platelet recruitment. Both of these arachidonic acid metabolites are inherently unstable due to their chemical structure. Tumor cells by contrast predominantly make more chemically stable prostaglandin E, which is the primary bioactive lipid associated with inflammation and oncogenesis. Pharmacological, clinical, and epidemiologic studies demonstrate that non-steroidal anti-inflammatory drugs (NSAIDs), which target cyclooxygenases, can help prevent cancer. Much of the molecular and biological impact of these drugs is generally accepted in the field. Cyclooxygenases catalyze the rate-limiting production of substrate used by all synthase molecules, including those that produce prostaglandins along with prostacyclin and thromboxane. Additional eicosanoid metabolites include lipoxygenases, leukotrienes, and resolvins that can also influence platelets, inflammation, and carcinogenesis. Our knowledge base and technology are now progressing toward identifying newer molecular and cellular interactions that are leading to revealing additional targets. This review endeavors to summarize new developments in the field.
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http://dx.doi.org/10.1007/s10555-018-9755-8DOI Listing
September 2018

Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome.

JAMA Oncol 2018 08;4(8):1085-1092

Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston.

Importance: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS.

Objective: To characterize the immune profile of premalignant lesions from a cohort of patients with LS.

Design, Setting, And Participants: Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017.

Main Outcomes And Measures: Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA.

Results: The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells, proinflammatory (tumor necrosis factor, interleukin 12) and checkpoint molecules (LAG3 [lymphocyte activation gene 3] and PD-L1 [programmed cell death 1 ligand 1]). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were comparable to hypermutant tumors and displayed additional checkpoint (CTLA4 [cytotoxic T-lymphocyte-associated protein 4]) and neoantigens involved in DNA damage response (ATM and BRCA1 signaling).

Conclusions And Relevance: These findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in LS.
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http://dx.doi.org/10.1001/jamaoncol.2018.1482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087485PMC
August 2018

Project ECHO: A Telementoring Program for Cervical Cancer Prevention and Treatment in Low-Resource Settings.

J Glob Oncol 2017 Oct 5;3(5):658-665. Epub 2016 Oct 5.

, , , , and , The University of Texas MD Anderson Cancer Center, Houston; , Su Clinica Familiar, Brownsville; , The University of Texas Medical Branch, Galveston, TX; , Hospital Central de Maputo, Maputo, Mozambique; , , Cancer Diseases Hospital, Lusaka, Zambia; , , , and , Hospital de Cancer de Barretos, Barretos; , , , and , Hospital Israelita Albert Einstein; , A.C. Camargo Cancer Center, Sao Paulo; , Federal University of Health Sciences/Santa Casa de Misericordia, Porto Alegre, Brazil; and , Universidad de la Republica, Montevideo, Uruguay; , Basic Health International, San Salvador, El Salvador; and , University of New Mexico, Albuquerque, NM.

Cervical cancer incidence and mortality rates are significantly higher in low- and middle-income countries compared with the United States and other developed countries. This disparity is caused by decreased access to screening, often coupled with low numbers of trained providers offering cancer prevention and treatment services. However, similar disparities are also found in underserved areas of the United States, such as the Texas-Mexico border, where cervical cancer mortality rates are 30% higher than in the rest of Texas. To address these issues, we have adopted the Project ECHO (Extension for Community Healthcare Outcomes) program, a low-cost telementoring model previously proven to be successful in increasing local capacity, improving patient management skills, and ultimately improving patient outcomes in rural and underserved areas. We use the Project ECHO model to educate local providers in the management of cervical dysplasia in a low-resource region of Texas and have adapted it to inform strategies for the management of advanced cervical and breast cancer in Latin America and sub-Saharan Africa. This innovative approach, using ECHO, is part of a larger strategy to enhance clinical skills and develop collaborative projects between academic centers and partners in low-resource regions.
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http://dx.doi.org/10.1200/JGO.2016.005504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646881PMC
October 2017

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma.

Cancer Res 2017 11 26;77(22):6119-6130. Epub 2017 Sep 26.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver mutations. mutations were present in AAHs from 4 of 22 (18%) of patients. mutations in AAH were only found in ever-smokers and were exclusive to -mutant cases. Integrative analysis revealed profiles expressed in -mutant cases () and -mutant cases () of AAH, or common to both sets of cases (suppressed ). Gene sets associated with suppressed antitumor (Th1; ) and elevated protumor () immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent or pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774855PMC
November 2017

Use of non-steroidal anti-inflammatory drugs in US adults: changes over time and by demographic.

Open Heart 2017;4(1):e000550. Epub 2017 Apr 28.

Baylor College of Medicine, USDA/ARS Children's Nutrition Research Center, Houston, Texas, USA.

Objective: Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are preventive against cardiovascular disease (CVD) and several cancer types, but long-term use has been associated with significant health risks, resulting in conflicting recommendations on NSAID use for prevention of CVD and cancer. Previous research indicates that aspirin use increases with age and CVD risk factors and that a large percentage of the US population regularly use analgesics, including NSAIDs, but there has not been a recent, in-depth assessment of NSAID use prevalence, changes in use over time or predictors of NSAID use in the USA.

Methods: We used the cross-sectional, National Health And Nutrition Examination Survey (NHANES) from 1988 to 1994 and three continuous cycles (1999-2004) to assess regular NSAID use prevalence, changes over time and predictors of regular NSAID use.

Results: Overall, regular NSAID use increased over time and varied by demographic features. Participants over 60 years of age, women, participants with high body mass index, increased waist circumference or heart disease were significantly more likely to be regular NSAID users. By contrast, non-Hispanic African American and Mexican American participants were significantly less likely to regularly use NSAIDs.

Conclusions: This study uses a nationally representative data set (NHANES) to provide an exploration of regular NSAID use patterns over time, highlighting several demographic, lifestyle and clinical conditions associated with regular NSAID use. Understanding who is likely to regularly use NSAIDs enables more targeted messaging both for increasing the preventive benefits and for limiting the toxicities associated with regular use of NSAIDs.
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http://dx.doi.org/10.1136/openhrt-2016-000550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471872PMC
April 2017

Mutational Heterogeneity in and Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis.

Clin Cancer Res 2017 Oct 23;23(19):5936-5947. Epub 2017 Jun 23.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal and driver mutations, thus challenging the prevailing monoclonal monocryptal model. High-depth next-generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas. Also, ultrasensitive genotyping of hotspot mutations of and was performed using nanofluidic PCRs in matched bulk biopsies ( = 59) and crypts ( = 591) from 18 adenomas and seven carcinomas and adjacent normal tissues. Multiple co-occurring truncal and driver alterations were uncovered in whole-lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultrasensitive genotyping of bulk biopsies and crypts revealed novel undetected mutations that were prominent among carcinomas, whereas abundant wild-type crypts were detected in adenomas. mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Nonrandom heterogeneity among crypts was also observed. The striking degree of nonrandom intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626604PMC
October 2017

Building trust and diversity in patient-centered oncology clinical trials: An integrated model.

Clin Trials 2017 Apr 7;14(2):170-179. Epub 2017 Feb 7.

5 Department of Life Sciences, College of Science and Engineering, Texas A&M University-Corpus Christi, Corpus Christi, TX, USA.

Background/aims: Trust is the cornerstone of clinical trial recruitment and retention. Efforts to decrease barriers and increase clinical trial participation among diverse populations have yielded modest results. There is an urgent need to better understand the complex interactions between trust and clinical trial participation. The process of trust-building has been a focus of intense research in the business community. Yet, little has been published about trust in oncology clinical trials or the process of building trust in clinical trials. Both clinical trials and business share common dimensions. Business strategies for building trust may be transferable to the clinical trial setting. This study was conducted to understand and utilize contemporary thinking about building trust to develop an Integrated Model of Trust that incorporates both clinical and business perspectives.

Methods: A key word-directed literature search of the PubMed, Medline, Cochrane, and Google Search databases for entries dated between 1 January 1985 and 1 September 2015 was conducted to obtain information from which to develop an Integrated Model of Trust.

Results: Successful trial participation requires both participants and clinical trial team members to build distinctly different types of interpersonal trust to effect recruitment and retention. They are built under conditions of significant emotional stress and time constraints among people who do not know each other and have never worked together before. Swift Trust and Traditional Trust are sequentially built during the clinical trial process. Swift trust operates during the recruitment and very early active treatment phases of the clinical trial process. Traditional trust is built over time and operates during the active treatment and surveillance stages of clinical trials. The Psychological Contract frames the participants' and clinical trial team members' interpersonal trust relationship. The "terms" of interpersonal trust are negotiated through the psychological contract. Contract renegotiation occurs in response to cyclical changes within the trust relationship throughout trial participation.

Conclusion: The Integrated Model of Trust offers a novel framework to interrogate the process by which diverse populations and clinical trial teams build trust. To our knowledge, this is the first model of trust-building in clinical trials that frames trust development through integrated clinical and business perspectives. By focusing on the process, rather than outcomes of trust-building diverse trial participants, clinical trials teams, participants, and cancer centers may be able to better understand, measure, and manage their trust relationships in real time. Ultimately, this may foster increased recruitment and retention of diverse populations to clinical trials.
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http://dx.doi.org/10.1177/1740774516688860DOI Listing
April 2017

Cross-species identification of genomic drivers of squamous cell carcinoma development across preneoplastic intermediates.

Nat Commun 2016 08 30;7:12601. Epub 2016 Aug 30.

Department of Bioinformatics &Computational Biology, University of Texas MD Anderson Cancer Center Houston, Houston, Texas 77030, USA.

Cutaneous squamous cell carcinoma (cuSCC) comprises 15-20% of all skin cancers, accounting for over 700,000 cases in USA annually. Most cuSCC arise in association with a distinct precancerous lesion, the actinic keratosis (AK). To identify potential targets for molecularly targeted chemoprevention, here we perform integrated cross-species genomic analysis of cuSCC development through the preneoplastic AK stage using matched human samples and a solar ultraviolet radiation-driven Hairless mouse model. We identify the major transcriptional drivers of this progression sequence, showing that the key genomic changes in cuSCC development occur in the normal skin to AK transition. Our data validate the use of this ultraviolet radiation-driven mouse cuSCC model for cross-species analysis and demonstrate that cuSCC bears deep molecular similarities to multiple carcinogen-driven SCCs from diverse sites, suggesting that cuSCC may serve as an effective, accessible model for multiple SCC types and that common treatment and prevention strategies may be feasible.
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http://dx.doi.org/10.1038/ncomms12601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013636PMC
August 2016

Ernest Hawk Discusses the NCI-Designated Cancer Centers' Joint Statement on the HPV Vaccine.

Authors:
Ernest T Hawk

Oncology (Williston Park) 2016 Jul;30(7):599-600

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July 2016

Genomic Landscape of Colorectal Mucosa and Adenomas.

Cancer Prev Res (Phila) 2016 06 24;9(6):417-27. Epub 2016 May 24.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas. Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The molecular basis of the adenoma-to-carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas. We analyzed the mutation profile and copy number changes of 25 adenomas and adjacent mucosa from 12 familial adenomatous polyposis patients using whole-exome sequencing and validated allelic imbalances (AI) in 37 adenomas using SNP arrays. We assessed for evidence of clonality and performed estimations on the proportions of driver and passenger mutations using a systems biology approach. Adenomas had lower mutational rates than did colorectal cancers and showed recurrent alterations in known cancer driver genes (APC, KRAS, FBXW7, TCF7L2) and AIs in chromosomes 5, 7, and 13. Moreover, 80% of adenomas had somatic alterations in WNT pathway genes. Adenomas displayed evidence of multiclonality similar to stage I carcinomas. Strong correlations between mutational rate and patient age were observed in at-risk mucosa and adenomas. Our data indicate that at least 23% of somatic mutations are present in at-risk mucosa prior to adenoma initiation. The genomic profiles of at-risk mucosa and adenomas illustrate the evolution from normal tissue to carcinoma via greater resolution of molecular changes at the inflection point of premalignant lesions. Furthermore, substantial genomic variation exists in at-risk mucosa before adenoma formation, and deregulation of the WNT pathway is required to foster carcinogenesis. Cancer Prev Res; 9(6); 417-27. ©2016 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941624PMC
June 2016

Mechanisms of nonsteroidal anti-inflammatory drugs in cancer prevention.

Semin Oncol 2016 Feb 10;43(1):65-77. Epub 2015 Sep 10.

The University of Texas MD Anderson Cancer Center, Division of Cancer Prevention and Population Sciences, Houston, TX, USA.

Various clinical and epidemiologic studies show that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclooxygenase inhibitors (COXIBs) help prevent cancer. Since eicosanoid metabolism is the main inhibitory targets of these drugs the resulting molecular and biological impact is generally accepted. As our knowledge base and technology progress we are learning that additional targets may be involved. This review attempts to summarize these new developments in the field.
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http://dx.doi.org/10.1053/j.seminoncol.2015.09.010DOI Listing
February 2016

Aspirin for Cancer Prevention: One Step Closer.

JAMA Oncol 2016 Jun;2(6):770-1

Division of Cancer Prevention and Population Sciences, Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston.

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http://dx.doi.org/10.1001/jamaoncol.2015.6395DOI Listing
June 2016

Germline Genetic Variants in the Wnt/β-Catenin Pathway as Predictors of Colorectal Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2016 Mar 25;25(3):540-6. Epub 2016 Jan 25.

Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: The Wnt/β-catenin signaling pathway plays a key role in stem cell maintenance in the colorectum. Rare high-penetrance genetic mutations in components of this pathway result in familial colorectal cancer, yet the impact of common, germline variants remains unknown.

Methods: We assessed 172 variants in 26 genes from the Wnt/β-catenin pathway in 809 colorectal cancer cases and 814 healthy controls, followed by replication of the top findings in another 691 cases and 775 controls. In silico informatic tools were used to predict functional effects of variants.

Results: Eighteen SNPs in the pathway were significantly associated with colorectal cancer risk (P < 0.05) in the discovery phase. We observed a significant dose-response increase in colorectal cancer risk by number of risk genotypes carried (P = 4.19 × 10(-8)). Gene-based analysis implicated CSNK1D (P = 0.014), FZD3 (P = 0.023), and APC (P = 0.027) as significant for colorectal cancer risk. In the replication phase, FZD3:rs11775139 remained significantly associated with reduced risk with a pooled OR of 0.85 [95% confidence interval (CI), 0.76-0.94, P = 0.001]. Although borderline significant in the replication population, APC:rs2545162 was highly significant in the pooled analysis-OR, 1.42; 95% CI, 1.16-1.74; P = 0.00085. Functional assessment identified several potential biologic mechanisms underlying these associations.

Conclusions: Our findings suggest that common germline variants in the Wnt/β-catenin pathway may be involved in colorectal cancer development.

Impact: These variants may be informative in colorectal cancer risk assessment to identify individuals at increased risk who would be candidates for screening.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-0834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779688PMC
March 2016

When "Effective" Prevention Agents Fail to Elicit Anticipated Effects: Challenges in Trial Design.

Cancer Prev Res (Phila) 2016 Feb 29;9(2):125-7. Epub 2015 Dec 29.

Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, MD Anderson Cancer Center, Houston, Texas.

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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0432DOI Listing
February 2016

Molecular cancer prevention: Current status and future directions.

CA Cancer J Clin 2015 Sep-Oct;65(5):345-83. Epub 2015 Aug 18.

Vice President and Division Head, Boone Pickens Distinguished Chair for Early Prevention of Cancer, Division of Cancer Prevention & Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX.

The heterogeneity and complexity of advanced cancers strongly support the rationale for an enhanced focus on molecular prevention as a priority strategy to reduce the burden of cancer. Molecular prevention encompasses traditional chemopreventive agents as well as vaccinations and therapeutic approaches to cancer-predisposing conditions. Despite challenges to the field, we now have refined insights into cancer etiology and early pathogenesis; successful risk assessment and new risk models; agents with broad preventive efficacy (eg, aspirin) in common chronic diseases, including cancer; and a successful track record of more than 10 agents approved by the US Food and Drug Administration for the treatment of precancerous lesions or cancer risk reduction. The development of molecular preventive agents does not differ significantly from the development of therapies for advanced cancers, yet it has unique challenges and special considerations given that it most often involves healthy or asymptomatic individuals. Agents, biomarkers, cohorts, overall design, and endpoints are key determinants of molecular preventive trials, as with therapeutic trials, although distinctions exist for each within the preventive setting. Progress in the development and evolution of molecular preventive agents has been steadier in some organ systems, such as breast and skin, than in others. In order for molecular prevention to be fully realized as an effective strategy, several challenges to the field must be addressed. Here, the authors provide a brief overview of the context for and special considerations of molecular prevention along with a discussion of the results from major randomized controlled trials.
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http://dx.doi.org/10.3322/caac.21287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820069PMC
December 2015

Urinary PGE-M in colorectal cancer: predicting more than risk?

Cancer Prev Res (Phila) 2014 Oct 28;7(10):969-72. Epub 2014 Jul 28.

Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Progress in cancer chemoprevention has been hindered by a lack of validated biomarkers of risk and interventive response. The identification of accurate, reliable, and easily measurable risk and response biomarkers within the field of cancer prevention could dramatically alter our approach to the disease. Colorectal cancer is associated with substantial morbidity and a limited 5-year survival rate for late-stage disease. The identification of biomarkers to predict (i) those most at risk of clinically significant colorectal neoplasia in conjunction with or building upon current risk models and/or (ii) those most likely to respond to potential colorectal chemopreventive agents, such as aspirin and NSAIDs, would significantly advance colorectal cancer risk management. Urinary PGE-M is an established indicator of systemic prostaglandin E2 production and has previously been demonstrated to predict risk of advanced colorectal neoplasia in a handful of studies. In the July 2014 issue, Bezawada and colleagues confirmed those earlier risk associations and demonstrated that PGE-M can also predict responsiveness to aspirin/NSAIDs in a small subset of women undergoing lower endoscopy in the Nurse's Health Study. PGE-M has the potential to define subsets of the population that may derive greater chemopreventive benefit from NSAIDs, as well as the potential to optimize the use of expensive and/or invasive screening tests. Additional larger and more diverse prospective studies meeting the criteria for phase IV biomarker studies are needed to advance the development of PGE-M as a noninvasive biomarker of both risk and chemopreventive response in populations at risk for colorectal cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-14-0215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185234PMC
October 2014

Convergence of nanotechnology and cancer prevention: are we there yet?

Cancer Prev Res (Phila) 2014 Oct 24;7(10):973-92. Epub 2014 Jul 24.

Division of Cancer Prevention & Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Nanotechnology is emerging as a promising modality for cancer treatment; however, in the realm of cancer prevention, its full utility has yet to be determined. Here, we discuss the potential of integrating nanotechnology in cancer prevention to augment early diagnosis, precision targeting, and controlled release of chemopreventive agents, reduced toxicity, risk/response assessment, and personalized point-of-care monitoring. Cancer is a multistep, progressive disease; the functional and acquired characteristics of the early precancer phenotype are intrinsically different from those of a more advanced anaplastic or invasive malignancy. Therefore, applying nanotechnology to precancers is likely to be far more challenging than applying it to established disease. Frank cancers are more readily identifiable through imaging and biomarker and histopathologic assessment than their precancerous precursors. In addition, prevention subjects routinely have more rigorous intervention criteria than therapy subjects. Any nanopreventive agent developed to prevent sporadic cancers found in the general population must exhibit a very low risk of serious side effects. In contrast, a greater risk of side effects might be more acceptable in subjects at high risk for cancer. Using nanotechnology to prevent cancer is an aspirational goal, but clearly identifying the intermediate objectives and potential barriers is an essential first step in this exciting journey.
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http://dx.doi.org/10.1158/1940-6207.CAPR-14-0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307396PMC
October 2014
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