Mapping of population disparities in the cholangiocarcinoma urinary metabolome

AbstractPhenotypic diversity in urinary metabolomes of different geographical populations has been recognized recently. In this study, urinary metabolic signatures from Western (United Kingdom) and South-East Asian (Thai) cholangiocarcinoma patients were characterized to understand spectral variability due to host carcinogenic processes and/or exogenous differences (nutritional, environmental and pharmaceutical). Urinary liquid chromatography mass spectroscopy (LC–MS) spectral profiles from Thai (healthy = 20 and cholangiocarcinoma = 14) and UK cohorts (healthy = 22 and cholangiocarcinoma = 10) were obtained and modelled using chemometric data analysis. Healthy metabolome disparities between the two distinct populations were primarily related to differences in dietary practices and body composition. Metabolites excreted due to drug treatment were dominant in urine specimens from cholangiocarcinoma patients, particularly in Western individuals. Urine from participants with sporadic (UK) cholangiocarcinoma contained greater levels of a nucleotide metabolite (uridine/pseudouridine). Higher relative concentrations of 7-methylguanine were observed in urine specimens from Thai cholangiocarcinoma patients. The urinary excretion of hippurate and methyladenine (gut microbial-host co-metabolites) showed a similar pattern of lower levels in patients with malignant biliary tumours from both countries. Intrinsic (body weight and body composition) and extrinsic (xenobiotic metabolism) factors were the main causes of disparities between the two populations. Regardless of the underlying aetiology, biological perturbations associated with cholangiocarcinoma urine metabolome signatures appeared to be influenced by gut microbial community metabolism. Dysregulation in nucleotide metabolism was associated with sporadic cholangiocarcinoma, possibly indicating differences in mitochondrial energy production pathways between cholangiocarcinoma tumour subtypes. Mapping population-specific metabolic disparities may aid in interpretation of disease processes and identification of candidate biomarkers.</jats:p

Cholangiocarcinoma: a guide for the nonspecialist

Cholangiocarcinoma (CCA) is a tumor with increasing prevalence around the world. The prevalence of CCA is highest in East Asia and most significantly in the countries through which the Mekong River flows, owing to the presence of liver flukes, which are consumed in raw fish dishes. Outside Asia, the causes of bile duct cancers for the most part are unknown. In this review, we assess the current state of knowledge in both fluke-associated and sporadic CCA, from etiological, diagnostic, and treatment perspectives

Cholangiocarcinoma: a guide for the nonspecialist

Munirah Alsaleh,1 Zoe Leftley,1 Thomas A Barbera,1 Paiboon Sithithaworn,2 Narong Khuntikeo,2 Watcharin Loilome,2 Puangrat Yongvanit,2 I Jane Cox,3 Nittaya Chamodol,2 Richard RA Syms,4 Ross H Andrews,1,2 Simon D Taylor-Robinson1 1Division of Surgery and Cancer, Imperial College London, London W2 INY, UK; 2Cholangiocarcinoma Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; 3Faculty of Life Sciences &amp; Medicine, King&rsquo;s College London, London SE5 9NT, UK; 4Department of Electrical and Electronic Engineering, Imperial College London, London SW7 2AZ, UK Abstract: Cholangiocarcinoma (CCA) is a tumor with increasing prevalence around the world. The prevalence of CCA is highest in East Asia and most significantly in the countries through which the Mekong River flows, owing to the presence of liver flukes, which are consumed in raw fish dishes. Outside Asia, the causes of bile duct cancers for the most part are unknown. In this review, we assess the current state of knowledge in both fluke-associated and sporadic CCA, from etiological, diagnostic, and treatment perspectives. Keywords: cholangiocarcinoma, etiology, diagnosis, treatment, bile duct

Grazer-induced responses in marine phytoplankton

Phytoplankton are the most important primary producers in the world’s oceans, yet little is known of how they avoid the constant threats from the pelagic grazers. From land it is well known that plants defend themselves by having thorns or producing compounds unpalatable to grazers. This thesis shows how different species of phytoplankton cope with different threats from pelagic grazers. In paper I the focus was on the dinoflagellate Alexandrium minutum, a producer of the highly potent neurotoxins paralytic shellfish toxins (PST). These toxins can cause mass mortalities in marine mammals and can be deadly to humans, who ingest the toxins via filter feeders that accumulate the toxins from algae in their diet. The suggested purpose of these toxins is to act as a defence against zooplankton grazers, like copepods. It has been shown that A. minutum is able to sense water borne cues from the copepods and respond by an increase in PST production. The results of paper I show that not only is A. minutum able to sense copepods, it can also recognize different species and respond by either increasing PST production or not. Cues from one of the copepod species tested, Centropages typicus, resulted in a more than 20 fold increase in PST, whereas another copepod, Pseudocalanus sp., did not have any effect on the PST content. It seems likely that A. minutum can recognize copepods that have the same distribution area as itself, these species would be the most significant grazers on A. minutum and a defence against them would benefit the alga. This strengthens the suggested role of PST as a grazer deterrent. Another group of substances that have been suggested to act as defence against grazers are the polyunsaturated aldehydes (PUA) produced by some phytoplankton, among others, diatoms. The role of PUA has been debated and various effects have been shown for a number of organisms. PUA has been shown to have negative effect on the reproduction of copepods, but results are contradictory. In paper II we investigate another possible defencive effect of PUA, as a structuring agent on the microbial community of bacteria and viruses. Bacteria can infect diatoms or compete for nutrients, and viral infections can terminate phytoplankton blooms. Compounds that affect these organisms can be of great benefit for the producing organism. The results in paper II show that PUA have no effect on either bacteria or viruses, and further questions the role of these compounds. Perhaps the most interesting findings in this thesis are the ones presented in paper III and IV, where diatoms are shown to use chain length plasticity as a defence against copepods. Previously, different factors such as nutrient uptake and flotation has been suggested to be the driving force behind chain formation, but chain formation as a defence has been suggested before. Here I present further support for this. The diatoms responded to cues from copepods by reducing their chain length, and thereby size, with reduced grazing as a result. Reducing chains to single cells would make the diatom Skeletonema marinoi to small for copepods to handle, while larger species like Thalassiosira rotula would still be large enough to be caught. But by reducing chain length the diatoms also reduce the encounter rate with grazers, and thus larger species like T. rotula can escape grazing. Lower grazing rates were also observed on single cells than longer chains. All diatoms did not respond to grazer cues in the same way, Chaetoceros affinis did not reduce chain length when subjected to copepods. C. affinis has long spines that may act a as a defence which could be the reason why it does not reduce its size. I suggest that chain length plasticity may be an evolutionarily adopted trait in chain forming diatoms and that size-selective predation may have played a key role in the evolution of chain formation and chain length plasticity in diatoms

Characterisation of the serum metabolic signature of cholangiocarcinoma in a United Kingdom cohort

Background A distinct serum metabonomic pattern has been previously revealed to be associated with various forms of liver disease. Here, we aimed to apply mass spectrometry to obtain serum metabolomic profiles from individuals with cholangiocarcinoma and benign hepatobiliary diseases to gain an insight into pathogenesis and search for potential early-disease biomarkers. Methods Serum samples were profiled using a hydrophilic interaction liquid chromatography platform, coupled to a mass spectrometer. A total of 47 serum specimens from 8 cholangiocarcinoma cases, 20 healthy controls, 8 benign disease controls (bile duct strictures) and 11 patients with hepatocellular carcinoma (as malignant disease controls) were included. Data analysis was performed using univariate and multivariate statistics. Results The serum metabolome disparities between the metabolite profiles from healthy controls and patients with hepatobiliary disease were predominantly related to changes in lipid and lipid-derived compounds (phospholipids, bile acids and steroids) and amino acid metabolites (phenylalanine). A metabolic pattern indicative of inflammatory response due to cirrhosis and cholestasis was associated with the disease groups. The abundance of phospholipid metabolites was altered in individuals with liver disease, particularly cholangiocarcinoma, but no significant difference was seen between profiles from patients with benign biliary strictures and cholangiocarcinoma. Conclusion The serum metabolome in cholangiocarcinoma exhibited changes in metabolites related to inflammation, altered energy production and phospholipid metabolism. This study serves to highlight future avenues for biomarker research in large-scale studies