Metabolic phenotype of bladder cancer

Metabolomics use in toxicology is rapidly increasing, particularly owing to advances in mass spectroscopy, which is widely used in the life sciences for phenotyping disease states. Toxicology has the advantage of having the disease agent, the toxicant, available for experimental induction of metabolomics changes monitored over time and dose. This review summarizes the different technologies employed and gives examples of their use in various areas of toxicology. A prominent use of metabolomics is the identification of signatures of toxicity – patterns of metabolite changes predictive of a hazard manifestation. Increasingly, such signatures indicative of a certain hazard manifestation are identified, suggesting that certain modes of action result in specific derangements of the metabolism. This might enable the deduction of underlying pathways of toxicity, which, in their entirety, form the Human Toxome, a key concept for implementing the vision of Toxicity Testing for the 21st century. This review summarizes the current state of metabolomics technologies and principles, their uses in toxicology and gives a thorough overview on metabolomics bioinformatics, pathway identification and quality assurance. In addition, this review lays out the prospects for further metabolomics application also in a regulatory context. Copyright © 2013 John Wiley & Sons, Ltd.

Review: Toxicometabolomics: Toxicometabolomics

Bladder cancer (BC) is a common cancer but diagnostic modalities, such as cystoscopy and urinary cytology, have limitations. Here, high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOFMS) was used to profile urine metabolites of 138 patients with BC and 121 control subjects (69 healthy people and 52 patients with hematuria due to non-malignant diseases). Multivariate statistical analysis revealed that the cancer group could be clearly distinguished from the control groups on the basis of their metabolomic profiles, even when the hematuric control group was included. Patients with muscle-invasive BC could also be distinguished from patients with non-muscle-invasive BC on the basis of their metabolomic profiles. Successive analyses identified 12 differential metabolites that contributed to the distinction between the BC and control groups, and many of them turned out to be involved in glycolysis and betaoxidation. The association of these metabolites with cancer was corroborated by microarray results showing that carnitine transferase and pyruvate dehydrogenase complex expressions are significantly altered in cancer groups. In terms of clinical applicability, the differentiation model diagnosed BC with a sensitivity and specificity of 91.3% and 92.5%, respectively, and comparable results were obtained by receiver operating characteristic analysis (AUC = 0.937). Multivariate regression also suggested that the metabolomic profile correlates with cancer-specific survival time. The excellent performance and simplicity of this metabolomics-based approach suggests that it has the potential to augment or even replace the current modalities for BC diagnosis.

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Diagnosis of bladder cancer and prediction of survival by urinary metabolomics.

Bladder cancer is one of the most prevalent cancers worldwide, but the treatment and management of this disease can be very successful if the disease is detected early The development of molecular assays that could diagnose bladder cancer accurately, and at an early stage, would be a significant advance Ideally, such molecular assays would be applicable to non-invasively obtained body fluids, and be designed not only for diagnosis but also for monitoring disease recurrence and response to treatment In this article, we assess the performance of current diagnostic assays for bladder cancer and discuss some of the emerging biomarkers that could be developed to augment current bladder cancer detection strategies

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Bladder Cancer Detection and Monitoring: Assessment of Urine- and Blood-Based Marker Tests

Large-scale metabolomics study requires a quantitative method to generate metabolome data over an extended period with high technical reproducibility We report a universal metabolome-standard (UMS) method, in conjunction with chemical isotope labeling liquid chromatography–mass spectrometry (LC–MS), to provide long-term analytical reproducibility and facilitate metabolome comparison among different data sets In this method, UMS of a specific type of sample labeled by an isotope reagent is prepared a priori The UMS is spiked into any individual samples labeled by another form of the isotope reagent in a metabolomics study The resultant mixture is analyzed by LC–MS to provide relative quantification of the individual sample metabolome to UMS UMS is independent of a study undertaking as well as the time of analysis and useful for profiling the same type of samples in multiple studies In this work, the UMS method was developed and applied for a urine metabolomics study of bladder cancer UMS of human ur

Development of a universal metabolome-standard method for long-term LC-MS metabolome profiling and its application for bladder cancer urine-metabolite-biomarker discovery.

Bladder cancer (BC) is one of the most common cancers and has a high mortality rate. However, both metabolite variations and metabolic pathways related to the pathogenic process of BC remain to be addressed, such results might contribute to early detection of the disease. (1)H nuclear magnetic resonance (NMR)-based metabolomics was applied to identify differences of serum metabolic profiles among BC, calculi patients and healthy subjects. Serum metabolic profiles of BC patients are distinctly different from those of calculi and healthy subjects. Compared with those from healthy subjects, serum samples from BC patients show decreased levels of isoleucine/leucine, tyrosine, lactate, glycine, citrate, as well as increased levels of lipids and glucose. The results reveal disturbed metabolic pathways of aromatic amino acids, glycolysis and citrate cycle, as well as lipogenesis metabolism in BC patients. Our work will be of potential benefit to understanding the pathogenic process of BC and will offer valuable information for noninvasive diagnosis of the disease.

NMR-based metabolomic analysis of human bladder cancer.

Objective To evaluate the efficacy and safety of intravesical instillation with gemcitabine after first-line intravesical chemotherapy failure, including mitomycin (MMC), epirubicin (EPB) and camptothecin (CPT), in the treatment of non-muscle-invasive bladder cancer (NMIBC). Methods From June 2007 to October 2008, 72 patients with NMIBC, who had tumor recurrence within one year of first-line intravesical chemotherapy, were assigned to 3 groups (24 cases each). Group A received intravesical gemcitabine in a dose of 1000 mg, Group B received 2000 mg gemcitabine, and Group C received original intravesical chemotherapy. The time of reccurrence and adverse effects were recorded. Results The 2-year tumor free survival rates of the 3 groups were 66.7%, 75.0% and 45.8%, respectively. The 2-year TFS rate of the patients who received gemcitabine was 70.8%, significantly higher than 45.8% of the patients treated by original chemotherapy. There was one case with renal function impairement in the groups A and B, respectively. There was no significant difference between the rates of low urinary tract symptoms in the 3 groups. No severe hematological side effects were observed in this study. Conclusion The intravescal chemotherapy with gemcitabine in patients with recurrent bladder tumor after first-line intravesical chemotherapy is effective and well tolerated, however, renal function should be routinely assessed.

[Evaluation of the efficacy and safety of intravesical instillation with gemcitabine after first-line intravesical chemotherapy failure in the treatment of non-muscle-invasive bladder cancer].

An improved bladder injection needle comprises a needle head, the needle head is connected with a Luer taper, and a push handle is formed on the Luer taper. The Luer taper is provided with a baffle and sleeved with a blocking sleeve, a needle tip is formed on the needle head, the inclined face of the needle tip is in an inwards-concave arc shape, and scale-shaped wrinkles are formed on the outer surface of the needle tip. Reinforcing ribs are formed on the inner surface of the needle head. Due to the fact that the inclined face of the needle tip is arranged to be in the inwards-concave arc shape, the angle of the needle tip initially penetrating into the body is reduced. In addition, due to the fact that the bionic fish scale shape is used for a week, the contact area between the needle tip and the skin in the piercing process is reduced, the sliding capacity of the needle tip is improved, contact between the needle tip and the pain nerve of the body is reduced, the needle tip can quickly pierce into the human body, and the pain of a patient is relieved.

Ming Cao

Papers

NMR-based metabolomic analysis of human bladder cancer.

[Evaluation of the efficacy and safety of intravesical instillation with gemcitabine after first-line intravesical chemotherapy failure in the treatment of non-muscle-invasive bladder cancer].

Improved bladder injection needle