Analytical metabolomics: nutritional opportunities for personalized health

Nutrition is the cornerstone of health; survival depends on acquiring essential nutrients, and dietary components can both prevent and promote disease. Metabolomics, the study of all small molecule metabolic products in a system, has been shown to provide a detailed snapshot of the body's processes at any particular point in time, opening up the possibility of monitoring health and disease, prevention and treatment. Metabolomics has the potential to fundamentally change clinical chemistry and, by extension, the fields of nutrition, toxicology and medicine. Technological advances, combined with new knowledge of the human genome and gut microbiome, have made and will continue to make possible earlier, more accurate, less invasive diagnoses, all while enhancing our understanding of the root causes of disease and leading to a generation of dietary recommendations that enable optimal health. This article reviews the recent contributions of metabolomics to the fields of nutrition, toxicology and medicine. It is expected that these fields will eventually blend together through development of new technologies in metabolomics and genomics into a new area of clinical chemistry: personalized medicine.     

美国国家癌症研究所(National Cancer Institute)--美国癌症研究和资助的主要机构

美国国家癌症研究所(National Cancer Institute,NCI)成立于1937年,是国立卫生研究院(National Institutes of Health,NIH)历史最为悠久的研究所,也是美国癌症研究和资助的主要机构。通过立法及增加对癌症研究的投入,NCI在癌症研究领域取得一些成绩,使肺癌、结直肠癌、乳腺癌及前列腺癌的死亡率持续下降,另在胰腺癌、卵巢癌、白血病和甲状腺癌等肿瘤的诊断和治疗方面也取得了巨大成就。新近NCI制定了到20l5年的奋斗目标：“消除痛苦、减少死亡”,并将主要策略由“寻找进而破坏(seekanddestory)”转为“锁定并且控制(target and control)”。为了实现上述目标,NCI提出必须加强基础研究,以利癌症的早期发现(discovery);以此为基础,将实验室的研究结果尽快用于临床,促进各种治疗措施的发展(development);加强癌症防治的公共卫生宣传,以利于健康资讯的发布(delivery)。本文将简述NCI的历史沿革、主要目标、组织结构、资金预算以及所取得的成就。     

HORA suite: a database and software for human metabolomics

HORA suite (Human blOod Range vAlidator) consists of a Java application used to validate the metabolomic analysis of human blood against a database that stores the normal plasma and serum range concentrations of metabolites. The goal of HORA is to find the metabolites that are outside the normal range and to show those not present in the list provided by the user, for different thresholds of concentration. Moreover it supplies a graphical interface to manage the data. The software can also be used to compare different metabolomic techniques. HORA is open-source software and it can be accessed at . A separate file contains instructions for the installation and a brief tutorial.     

Complexity and pitfalls of mass spectrometry-based targeted metabolomics in brain research

Current quantitative metabolomic research in brain tissue is challenged by several analytical issues. To compare data of metabolite pattern, ratios of individual metabolite concentrations and composed classifiers characterizing a distinct state, standardized workup conditions, and extraction medium are crucial. Differences in physicochemical properties of individual compounds and compound classes such as polarity determine extraction yields and, thus, ratios of compounds with varying properties. Also, variations in suppressive effects related to coextracted matrix components affect standards or references and their concentration-dependent responses.The selection of a common tissue extraction protocol is an ill-posed problem because it can be regarded as a multiple objective decision depending on factors such as sample handling practicability, measurement precision, control of matrix effects, and relevance of the chemical assay. This study systematically evaluates the impact of extraction solvents and the impact of the complex brain tissue on measured metabolite levels, taking into account ionization efficiency as well as challenges encountered in the trace-level quantification of the analytes in brain matrices. In comparison with previous studies that relied on nontargeted platforms, consequently emphasizing the global behavior of the metabolomic fingerprint, here we focus on several series of metabolites spanning over extensive polarity, concentration, and molecular mass ranges.     

Trace elements under the spotlight: A powerful nutritional tool in cancer

Cancer is the second leading cause of death worldwide. Research on the relationships between trace elements (TE) and the development of cancer or its prevention is a field that is gaining increasing relevance. This review provides an evaluation of the effects of TE (As, Al, B, Cd, Cr, Cu, F, I, Pb, Li, Mn, Hg, Mo, Ni, Se, Si, Sn, V and Zn) intake and supplementation in cancer risk and prevention, as well as their interactions with oncology treatments. Advancements in the knowledge of TE, their dietary interactions and their main food sources can provide patients with choices that will help them to improve their quality of life and therapy outcomes. This approach could open new opportunities for treatments based on the integration of conventional therapies (chemotherapy, radiotherapy, and immunotherapy) and dietary interventions that provide advanced personalized treatments.     

Potential role of metabolomics in the improvement of research on traditional African medicine

The global market for herbal medicine is growing steadily. The usage of herbal medicine is particularly common in many parts of Africa; the World Health Organization estimates that approximately 80% of Africans rely on traditional African medicines (TAMs) for treating various diseases. TAMs hold promise in preventive treatment, early disease intervention and personalized medicine. However, clinical integration of TAMs is restricted due to limited information concerning their characterization. Presently, many studies on TAMs utilize a reductionist approach, making it extremely difficult to understand the holistic modifying effects that these therapeutic agents may have on biological systems. Fortunately, emerging technologies such as metabolomics platforms adopt a ⿿top-down⿿ strategy that permits a holistic evaluation of the components, metabolic pathways and biomarkers modified by TAMs, which can aid in addressing common concerns over safety and toxicity, while also ensuring that quality control standards are met. Metabolomics approaches may also be beneficial for advancing our understanding of the efficacy and mechanism of action of TAMs, and may contribute to the advancement of research and drug discovery, early diagnosis, preventive treatment and TAMs-driven personalized medicine in Africa. This review also considers the main challenges that may hinder the adoption and integration of metabolomics approaches in research on TAMs in Africa and suggests possible solutions.     

Towards quantitative metabolomics of mammalian cells: Development of a metabolite extraction protocol

Metabolomics aims to quantify all metabolites within an organism, thereby providing valuable insight into the metabolism of cells. To study intracellular metabolites, they are first extracted from the cells. The ideal extraction procedure should immediately quench metabolism and quantitatively extract all metabolites, a significant challenge given the rapid turnover and physicochemical diversity of intracellular metabolites. We have evaluated several quenching and extraction solutions for their suitability for mammalian cells grown in suspension. Quenching with 60% methanol (buffered or unbuffered) resulted in leakage of intracellular metabolites from the cells. In contrast, quenching with cold isotonic saline (0.9% [w/v] NaCl, 0.5 °C) did not damage cells and effectively halted conversion of ATP to ADP and AMP, indicative of metabolic arrest. Of the 12 different extraction methods tested, cold extraction in 50% aqueous acetonitrile was superior to other methods. The recovery of a mixture of standards was excellent, and the concentration of extracted intracellular metabolites was higher than for the other methods tested. The final protocol is easy to implement and can be used to study the intracellular metabolomes of mammalian cells.     

Nanostructure Initiator Mass Spectrometry for tissue imaging in metabolomics: future prospects and perspectives

Mass spectrometry-based metabolomics provides a new approach to interrogate mechanistic biochemistry related to natural processes such as health and disease. Physiological and pathological conditions, however, are characterized not only by the identities and concentrations of metabolites present, but also by the location of metabolites within a tissue. Unfortunately, most relevant MS platforms in metabolomics can only measure samples in solution, therefore metabolites are typically extracted by tissue homogenization. Recent developments of imaging-MS technologies, however, have allowed particular metabolites to be spatially localized within biological tissues. In this context, Nanostructure-Initiator Mass Spectrometry (NIMS), a matrix-free technique for surface-based analysis, has proven an alternative approach for tissue imaging of metabolites. Here we review the basic principles of NIMS for tissue imaging and show applications that can complement LC/MS and GC/MS-based metabolomic studies investigating the mechanisms of fundamental biological processes. In addition, the new surface modifications and nanostructured materials herein presented demonstrate the versatility of NIMS surface to expand the range of detectable metabolites.     

Cancer incidence in Iran in 2014: Results of the Iranian National Population-based Cancer Registry

BackgroundWe aimed to report, for the first time, the results of the Iranian National Population-based Cancer Registry (INPCR) for the year 2014.MethodsTotal population of Iran in 2014 was 76,639,000. The INPCR covered 30 out of 31 provinces (98% of total population). It registered only cases diagnosed with malignant new primary tumors. The main sources for data collection included pathology center, hospitals as well as death registries. Quality assessment and analysis of data were performed by CanReg-5 software. Age standardized incidence rates (ASR) (per 100,000) were reported at national and subnational levels.ResultsOverall, 112,131 new cancer cases were registered in INPCR in 2014, of which 60,469 (53.9%) were male. The diagnosis of cancer was made by microscopic confirmation in 76,568 cases (68.28%). The ASRs of all cancers were 177.44 and 141.18 in male and female, respectively. Cancers of the stomach (ASR = 21.24), prostate (18.41) and colorectum (16.57) were the most common cancers in men and the top three cancers in women were malignancies of breast (34.53), colorectum (11.86) and stomach (9.44). The ASR of cervix uteri cancer in women was 1.78. Our findings suggested high incidence of cancers of the esophagus, stomach and lung in North/ North West of Iran.ConclusionOur results showed that Iran is a medium-risk area for incidence of cancers. We found differences in the most common cancers in Iran comparing to those reported for the World. Our results also suggested geographical diversities in incidence rates of cancers in different subdivisions of Iran.     

Cancer in adolescents and young adults: National incidence and characteristics in Japan

ObjectiveAdolescents and young adults (AYA) with cancer are confronted with unique challenges in areas of paramount concern within their age group, such as fertility, education, career, and delayed and long-term effects of treatment. However, the extent and depth of the problem has never been examined in the Japanese population. The aim of this study was to describe the status of cancer patients in the AYA population, using data from the hospital-based cancer registry (HBCR).Study designPatients included in the HBCR from January 2011 to December 2014 were included in this study to evaluate the incidence and cancer distribution trends among AYA. The total number and the proportion of AYA (15–39 years of age) stratified by sex, age, and cancer type were obtained. The incidence of age-specific cancer among AYA was also calculated.ResultsWe identified 30,394 male (35.1%) and 56,100 female (64.9%) cancer patients in the population, which collectively constituted about 3% of all invasive cancer cases. The incidence of cancer in AYA was estimated as 86.2 per 100,000 per year, and increased with age. The most affected population was women between 35 and 39 years of age (35%). Breast cancer was the most common type of cancer, followed by cervical, uterine, and thyroid cancers.ConclusionA substantial number of AYA are diagnosed with cancer every year. The distribution of cancer types in AYA was dependent on age and sex. These diversities in cancer types can inform researchers and policy makers to fine-tune their studies and policies.     

Untargeted metabolomics: an overview of its usefulness and future potential in prenatal diagnosis

ABSTRACT

Introduction: Metabolomics opens up new avenues for biomarker discovery in different branches of medicine, including perinatology. Chromosomal aberration, preterm delivery (PTD), congenital heart defects, spina bifida, chorioamnionitis, and low birth weight are the main perinatal pathologies. Investigations using untargeted metabolomics have found the candidate metabolites for diagnostic biomarkers.

Areas covered: This review describes areas of prenatal diagnosis in which untargeted metabolomics has been used. Data on the disease, type of sample, techniques used, number of samples used in the study, and metabolites obtained including the sign of their regulation are summarized.

Expert commentary: Untargeted metabolomics is a powerful tool which can shed a new light on prenatal diagnostics. It helps to discover affected metabolic pathways what may help to reveal disease pathogenesis and propose potential biomarkers. Among others, glycerol and 2- and 3-hydroxybutyrate were proposed as markers of chromosomal aberration. Serum metabolic signature of PTD was characterized by increased lipids and decreased levels of hypoxanthine, tryptophane, and pyroglutamic acid. Lower level lipids and vitamin D3 metabolites together with increased bilirubin level in maternal serum were associated with macrosomia. However, to give a real value to those assays and allow their clinical application multicenter, large cohort validation studies are necessary.     

Elucidating tumor-stromal metabolic crosstalk in colorectal cancer through integration of constraint-based models and LC-MS metabolomics

Colorectal cancer (CRC) is a major cause of morbidity and mortality in the United States. Tumor-stromal metabolic crosstalk in the tumor microenvironment promotes CRC development and progression, but exactly how stromal cells, in particular cancer-associated fibroblasts (CAFs), affect the metabolism of tumor cells remains unknown. Here we take a data-driven approach to investigate the metabolic interactions between CRC cells and CAFs, integrating constraint-based modeling and metabolomic profiling. Using metabolomics data, we perform unsteady-state parsimonious flux balance analysis to infer flux distributions for central carbon metabolism in CRC cells treated with or without CAF-conditioned media. We find that CAFs reprogram CRC metabolism through stimulation of glycolysis, the oxidative arm of the pentose phosphate pathway (PPP), and glutaminolysis, as well as inhibition of the tricarboxylic acid cycle. To identify potential therapeutic targets, we simulate enzyme knockouts and find that CAF-treated CRC cells are especially sensitive to inhibitions of hexokinase and glucose-6-phosphate, the rate limiting steps of glycolysis and oxidative PPP. Our work gives mechanistic insights into the metabolic interactions between CRC cells and CAFs and provides a framework for testing hypotheses towards CRC-targeted therapies.     

Metabolic engineering of flavonoids in tomato (Solanum lycopersicum): the potential for metabolomics

Flavonoids comprise a large and diverse group of polyphenolic plant secondary metabolites. In plants, flavonoids play important roles in many biological processes such as pigmentation of flowers, fruits and vegetables, plant-pathogen interactions, fertility and protection against UV light. Being natural plant compounds, flavonoids are an integral part of the human diet and there is increasing evidence that dietary polyphenols are likely candidates for the observed beneficial effects of a diet rich in fruits and vegetables on the prevention of several chronic diseases. Within the plant kingdom, and even within a single plant species, there is a large variation in the levels and composition of flavonoids. This variation is often due to specific mutations in flavonoid-related genes leading to quantitative and qualitative differences in metabolic profiles. The use of such specific flavonoid mutants with easily scorable, visible phenotypes has led to the isolation and characterisation of many structural and regulatory genes involved in the flavonoid biosynthetic pathway from different plant species. These genes have been used to engineer the flavonoid biosynthetic pathway in both model and crop plant species, not only from a fundamental perspective, but also in order to alter important agronomic traits, such as flower and fruit colour, resistance, nutritional value. This review describes the advances made in engineering the flavonoid pathway in tomato (Solanum lycopersicum). Three different approaches will be described; (I) Increasing endogenous tomato flavonoids using structural or regulatory genes; (II) Blocking specific steps in the flavonoid pathway by RNA interference strategies; and (III) Production of novel tomato flavonoids by introducing novel branches of the flavonoid pathway. Metabolite profiling is an essential tool to analyse the effects of pathway engineering approaches, not only to analyse the effect on the flavonoid composition itself, but also on other related or unrelated metabolic pathways. Metabolomics will therefore play an increasingly important role in revealing a more complete picture of metabolic perturbation and will provide additional novel insights into the effect of the introduced genes and the role of flavonoids in plant physiology and development.     

The future excess fraction of occupational cancer among those exposed to carcinogens at work in Australia in 2012

BackgroundStudies in other countries have generally found approximately 4% of current cancers to be attributable to past occupational exposures. This study aimed to estimate the future burden of cancer resulting from current occupational exposures in Australia.MethodsThe future excess fraction method was used to estimate the future burden of occupational cancer (2012–2094) among the proportion of the Australian working population who were exposed to occupational carcinogens in 2012. Calculations were conducted for 19 cancer types and 53 cancer-exposure pairings, assuming historical trends and current patterns continued to 2094.ResultsThe cohort of 14.6 million Australians of working age in 2012 will develop an estimated 4.8 million cancers during their lifetime, of which 68,500 (1.4%) are attributable to occupational exposure in those exposed in 2012. The majority of these will be lung cancers (n = 26,000), leukaemias (n = 8000), and malignant mesotheliomas (n = 7500).ConclusionsA significant proportion of future cancers will result from occupational exposures. This estimate is lower than previous estimates in the literature; however, our estimate is not directly comparable to past estimates of the occupational cancer burden because they describe different quantities – future cancers in currently exposed versus current cancers due to past exposures. The results of this study allow us to determine which current occupational exposures are most important, and where to target exposure prevention.     

The future excess fraction of cancer due to lifestyle factors in Australia

BackgroundMany cancers are caused by exposure to lifestyle, environmental, and occupational factors. Earlier studies have estimated the number of cancers occurring in a single year which are attributable to past exposures to these factors. However, there is now increasing appreciation that estimates of the future burden of cancer may be more useful for policy and prevention. We aimed to calculate the future number of cancers expected to arise as a result of exposure to 23 modifiable risk factors.MethodsWe used the future excess fraction (FEF) method to estimate the lifetime burden of cancer (2016–2098) among Australian adults who were exposed to modifiable lifestyle, environmental, and occupational risk factors in 2016. Calculations were conducted for 26 cancer sites and 78 cancer-risk factor pairings.ResultsThe cohort of 18.8 million adult Australians in 2016 will develop an estimated 7.6 million cancers during their lifetime, of which 1.8 million (24%) will be attributable to exposure to modifiable risk factors. Cancer sites with the highest number of future attributable cancers were colon and rectum (n = 717,700), lung (n = 380,400), and liver (n = 103,200). The highest number of future cancers will be attributable to exposure to tobacco smoke (n = 583,500), followed by overweight/obesity (n = 333,100) and alcohol consumption (n = 249,700).ConclusionA significant proportion of future cancers will result from recent levels of exposure to modifiable risk factors. Our results provide direct, pertinent information to help determine where preventive measures could best be targeted.