Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer.

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C

Molecular cancer prevention: Current status and future directions.

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.

Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man.

Liver-derived acute phase proteins (APPs) emerged as powerful predictors of cardiovascular disease and cardiovascular events, but their functional role in atherosclerosis remains enigmatic. We report that the gp130 receptor, which is a key component of the inflammatory signaling pathway within hepatocytes, influences the risk of atherosclerosis in a hepatocyte-specific gp130 knockout. Mice on an atherosclerosis-prone genetic background exhibit less aortic atherosclerosis (P < 0.05) with decreased plaque macrophages (P < 0.01). Translating these findings into humans, we show that genetic variation within the human gp130 homologue, interleukin 6 signal transducer (IL6ST), is significantly associated with coronary artery disease (CAD; P < 0.05). We further show a significant association of atherosclerotic disease at the ostium of the coronary arteries (P < 0.005) as a clinically important and heritable subphenotype in a large sample of families with myocardial infarction (MI) and a second independent population-based cohort. Our results reveal a central role of a hepatocyte-specific, gp130-dependent acute phase reaction for plaque development in a murine model of atherosclerosis, and further implicate IL6ST as a genetic susceptibility factor for CAD and MI in humans. Thus, the acute phase reaction should be considered an important target for future drug development in the management of CAD.

Cancer chemoprevention: successes and failures.

BACKGROUND: Cancer has traditionally been considered a single disease, but it is now known to be far more complex, with an unfolding etiology. In less than 2 centuries, hundreds--if not thousands--of drugs for the treatment of cancer and for palliative care have been developed and tested, with 143 having achieved approval by the US Food and Drug Administration (MediLexicon International; "Cancer Drugs & Oncology Drugs," http://www.medilexicon.com/drugs-list/cancer.php). Just 13 agents have been approved, however, for treating precancerous lesions or for reducing risk. CONTENT: Nonsteroidal antiinflammatory drugs, vitamins, food constituents and spice components, antidiabetic drugs, ω-3 fatty acids, and fiber are just a few of the many classes of compounds that have been tested for their cancer-preventive potential. We highlight some of the agents that have been scrutinized by way of randomized clinical trials in humans for their cancer prevention potential. We summarize the major definitive cancer chemoprevention studies that (a) were successful in demonstrating efficacy and ultimately received regulatory approval; (b) were not successful in demonstrating efficacy or had unacceptable toxicities, but from which the field has learned important lessons; and (c) showed compelling efficacy against surrogate end points but failed to achieve regulatory approval because of a lack of consensus regarding the relevance of those end points to clinical benefit. SUMMARY: Chemopreventive studies have provided new insights into early disease pathogenesis, stimulated new risk assessments and models, fostered important research in end point biomarkers, and led to 13 approved agents. The development of safe and effective chemopreventive agents holds tremendous potential for reducing the burden of cancer.

From Premalignant Biology to Precision Interception: Connecting the Dots with a Curated Collection of Invited Articles.

Nearly all cancers have identifiable histologically defined precursors known as precancers. These precancers offer a window of opportunity to intercept the neoplastic process to prevent its development into invasive cancer. However, lack of knowledge regarding the evolution of precancers and the microenvironmental pressures shaping them precludes efforts to intercept them. Technological developments over the past decade have facilitated the study of precancers at a previously unattainable resolution. Calls for a national PreCancer Atlas effort incorporating these technologies were heeded in 2018, with the launch of the Human Tumor Atlas Network (HTAN) as part of the Beau Biden National Cancer Moonshot. Since then, five funded HTAN groups have focused their efforts on profiling precancers from breast, colon, skin, and lung. In this time, what progress has been made? What is next for HTAN and the field of premalignant biology? And are there lessons that individual investigators and the larger prevention field can learn from this initial effort to accelerate the development of novel early detection methods, risk prediction biomarkers, and interception agents? A special collection of invited reviews by experts in cancer evolution, systems biology, immunology, cancer genetics, preventive agent development, among other areas, attempts to answer these questions.

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

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.

Genetic determinants of hypertension: an update.

Hypertension represents a global public health burden. In addition to the rarer Mendelian forms of hypertension, classic genetic studies have documented a significant heritable component to the most common form, essential hypertension (EH). Extensive efforts are under way to elucidate the genetic basis of this disease. Recently, a new form of Mendelian hypertension has been identified, pharmacogenetic association studies in hypertensive patients have identified novel gene-by-drug interactions, and the first genome-wide association studies of EH have been published. New findings in consomic and congenic rat models also offer new clues to the genetic architecture of this complex phenotype. In this review, the authors summarize and evaluate the most recent findings related to hypertension gene identification.

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

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-1ß, 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.

A locus on chromosome 10 influences C-reactive protein levels in two independent populations.

High sensitivity C-reactive protein (hsCRP) is an independent risk factor for cardiovascular disease, such as stroke or coronary artery disease. Genetic factors influence significantly the inter-individual variability of hsCRP. The aim of this study was to identify genomic regions influencing hsCRP levels. A genome scan was performed in two independent studies of Caucasian populations, namely 513 Western-European families ascertained for myocardial infarction (n = 1,406) and 120 French-Canadian families diagnosed with hypertension (n = 758). In the myocardial infarction families, 31% of the inter-individual variation of hsCRP levels was explained by genetic factors (P = 0.0000015) and loci influencing hsCRP were identified on chromosomes 10 (at 141 cM) and 5 (at 150 cM) with multipoint LOD scores of 3.15 and 2.23, respectively. An additional suggestive signal was detected on chromosome 2 in subset analyses. A similar degree of heritability has been observed in a second independent population of French-Canadian hypertensive families for hsCRP (30%) and linkage results for chromosome 10 were confirmed with maximum LOD score of 2.7. We identified a chromosomal region in two independent populations which influences hsCRP in addition to several unique regions. This provides targets for the identification of genes involved in the regulation of hsCRP and the development and progression of vascular disease, including stroke.

Linkage analysis for complex diseases using variance component analysis: SOLAR.

Variance component linkage analysis has become one of the most popular tools for the analysis of poly genic phenotypes. In particular for cardiovascular disease, such as coronary artery disease and myocardial infarction, variance component analysis holds some unique advantages. This analysis approach is versatile, affording the user the ability to incorporate the interplay between risk factors, genetic susceptibility, the effect of environmental factors, or the joint analysis of multiple phenotypes in the analysis. In this chapter, we present as an introduction the statistical background of variance component analysis as implemented in the genetic analysis package SOLAR.

Functional genomics and its implications for molecular medicine.

Technological development in genetics and genomics provides unprecedented possibilities to identify the underlying molecular basic of many common diseases. With the availability of the human genome sequence and growing information on the most frequent DNA variations combined with the molecular analysis on the RNA expression and protein level, diseases might be characterized in the future at the molecular level. Describing gene function anf the specific role of DNA, RNA, and proteins in the disease process provides novel diagnosis tools and treatment. Ultimately how the unique genetic signature of an individual influences the risk and prognosis of disease will be the basis for individualized medicine in the years to come.

Cancer Prevention Recommendations: Impact of Adherence.

OBJECTIVES: To review the relationship between adherence to cancer prevention guidelines published by the American Cancer Society and the World Cancer Research Fund/American Institute for Cancer Research and reductions in cancer incidence, cancer mortality, cardiovascular mortality, and overall mortality. DATA SOURCES: Current cancer prevention guidelines published by the American Cancer Society and the American Institute for Cancer Research, journal articles published between 2004 and 2016, and internet resources. CONCLUSION: Evidence from a number of large observational studies indicates that following current cancer prevention recommendations in a comprehensive manner results in significant reductions in both cancer risk and cancer mortality, as well as in cardiovascular mortality and overall mortality. IMPLICATIONS FOR NURSING PRACTICE: Nurses can take the lead in familiarizing patients and families with established cancer prevention recommendations and resources that may assist patients in implementing them comprehensively in their daily lives, as well as in discussing the substantial health benefits of adhering to the recommendations.

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

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.

Genetics, genomics and the power of stem cells to identify novel treatment options in complex diseases.

The advances in human genetics enabled through the implementation of the latest sequencing technologies have the potential to dramatically change the landscape of medicine. As we decipher the polymorphic structure of the genome, the next challenge will focus on understanding the complex functional implications in the context of health and disease. Multiple approaches will be necessary to evaluate genome variation. While computational analyses serve as a starting point and can predict functional effects in silico, further direct functional studies will be required. The development of technologies to generate induced pluripotent stem cells represents one of these approaches. With growing evidence that these cells and derived tissues resemble phenotypes observed in patients, this approach holds tremendous potential for both diagnosis and treatment. While further studies are required to better understand the underlying mechanisms and to improve the methodology for generating induced pluripotent stem cells, this technology appears to be a powerful tool for the functional evaluation of genome variation, drug screening, risk prediction and advanced diagnostics.

The role of genomics in the neonatal ICU.

Results of both the Human Genome and International HapMap Projects have provided the technology and resources necessary to enable fundamental advances through the study of DNA sequence variation in almost all fields of medicine, including neonatology. Genome-wide association studies are now practical, and the first of these studies are appearing in the literature. This article provides the reader with an overview of the issues in technology and study design relating to genome-wide association studies and summarizes the current state of association studies in neonatal ICU populations with a brief review of the relevant literature. Future recommendations for genomic association studies in neonatal ICU populations are also provided.

Genotyping platforms for mass-throughput genotyping with SNPs, including human genome-wide scans.

The completion of the Human Genome Project (HGP) in 2003 brought the scientific community one step closer to identifying the genes underlying common, polygenic diseases. Prior to this achievement, the goal of identifying the genetic factors responsible for diseases presenting substantial public health burdens was elusive. Although the theoretical foundation for disease association studies had been discussed before the completion of the HGP, obstacles remained at that time before such studies could be considered feasible. One of these obstacles was the identification and mapping of numerous polymorphisms that could be easily and inexpensively typed. However, this challenge was overcome with the sequencing of the human genome and the subsequent cataloging of single-nucleotide polymorphisms (SNPs). The challenge then became how to rapidly and cost-effectively assay a dense set of these SNPs in the large number of samples required for disease association studies of complex traits. This challenge has been recently met as well, with the commercial offering of mass-throughput oligonucleotide array-based genotyping platforms at affordable prices. These platforms have made genome-wide association scans a reality and bring us closer than ever to elucidating the genetic mechanisms of complex disease. Here, we discuss the need for mass-throughput genotyping and then review and evaluate various platforms now available to investigators wishing to undertake high-throughput genotyping projects with SNPs, particularly genome-wide association scans.

IL6 gene-wide haplotype is associated with susceptibility to acute lung injury.

Experimental and clinical studies support the key role of interleukin 6 (IL-6), a potent proinflammatory cytokine, in the development of acute lung injury (ALI). Plasma IL-6 levels are influenced mainly by genetic determinants, and a -174G/C polymorphism of the gene has been recently associated with susceptibility to ALI. Here we aimed to validate the association of the IL6 gene with ALI in a case-control sample from Spain. DNA was isolated from 67 consecutive patients who fulfilled international criteria for severe sepsis and for ALI and 96 population-based controls drawn from the general population. Genotypes of the -174G/C polymorphism along with other 14 tagging variants of the IL6 gene were evaluated. Twenty polymorphisms unlinked to IL6 gene were additionally compared between cases and controls to rule out population stratification. None of the individual single-nucleotide polymorphisms was significantly associated with susceptibility to ALI. However, we found that a common haplotype from -1363 to +4835 from the transcription start site, and spanning the gene, conferred risk for susceptibility to ALI (odds ratio, 2.73; 95% confidence interval, 1.39-5.37; P = 0.003). Adjustment for relevant covariates did not modify this result. These data support the association of the IL6 gene with ALI susceptibility and illustrate the value of haplotype analysis as a robust approach for evaluating IL6 gene effects in association studies.