0000000000337188
AUTHOR
M. Carmen Martínez-bisbal
Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer
Metabolism reprogramming is considered a hallmark of cancer. The study of bladder cancer (BC) metabolism could be the key to developing new strategies for diagnosis and therapy. This work aimed to identify tissue and urinary metabolic signatures as biomarkers of BC and get further insight into BC tumor biology through the study of gene-metabolite networks and the integration of metabolomics and transcriptomics data. BC and control tissue samples (n = 44) from the same patients were analyzed by High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance and microarrays techniques. Besides, urinary profiling study (n = 35) was performed in the same patients to identify a metabolomic profi…
Differentiation between Brain Metastasis and Glioblastoma using MRI and two-dimensional Turbo Spectroscopic Imaging data
In this paper we propose a novel technique to differentiate brain metastases from high-grade gliomas, which represent the most aggressive and common brain lesions. In spite of the significant progresses achieved in the field of MRI in the last decades, the differentiation between these two types of tumors is still a challenge as they show a similar appearance on MRI images, but require a completely different therapeutic treatment. Here, we show that such a differentiation is actually possible and can be obtained by making use of MRI as well as of two-dimensional Turbo Spectroscopic Imaging (2D-TSI) information. Specifically, the proposed technique consists of three steps: we first detect th…
Differentiation between brain metastases and glioblastoma multiforme based on MRI, MRS and MRSI
Brain metastases and glioblastoma multiforme are the most aggressive and common brain tumours in adults and they require a different clinical management. Anatomical magnetic resonance imaging (MRI) or clinical history, cannot always clearly distinguish between them. This study describes and verifies the use of magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging (MRSI) in combination with MRI for differential diagnosis of glioblastomas and metastases. Feature selection methods are applied to the magnetic resonance (MR) spectra of 121 patients and relevant features are detected. Different classification methods are used to distinguish glioblastoma multiforme and…
Development of a three-dimensional cell culture system based on microfluidics for nuclear magnetic resonance and optical monitoring
A new microfluidic cell culture device compatible with real-time nuclear magnetic resonance (NMR) is presented here. The intended application is the long-term monitoring of 3D cell cultures by several techniques. The system has been designed to fit inside commercially available NMR equipment to obtain maximum readout resolution when working with small samples. Moreover, the microfluidic device integrates a fibre-optic-based sensor to monitor parameters such as oxygen, pH, or temperature during NMR monitoring, and it also allows the use of optical microscopy techniques such as confocal fluorescence microscopy. This manuscript reports the initial trials culturing neurospheres inside the micro…
1H and 13C HR-MAS spectroscopy of intact biopsy samples ex vivo and in vivo 1H MRS study of human high grade gliomas.
High-resolution magic angle spinning (HR-MAS) one- and two-dimensional 1H and 13C nuclear magnetic resonance (NMR) spectroscopy has been used to study intact glioblastoma (GBM) brain tumour tissue. The results were compared with in vitro chemical extract and in vivo spectra. The resolution of 1H one-dimensional, 1H TOCSY and 13C HSQC HR-MAS spectra is comparable to that obtained on perchloric extracts. 13C HSQC HR-MAS spectra have been particularly useful for the identification of 37 different metabolites in intact biopsy tumours, excluding water and DSS components. To our knowledge, this is the most detailed assignment of biochemical compounds obtained in intact human tissue, in particular…
Fast nosological imaging using canonical correlation analysis of brain data obtained by two-dimensional turbo spectroscopic imaging.
A new fast and accurate tissue typing technique has recently been successfully applied to prostate MR spectroscopic imaging (MRSI) data. This technique is based on canonical correlation analysis (CCA), a statistical method able to simultaneously exploit the spectral and spatial information characterizing the MRSI data. Here, the performance of CCA is further investigated by using brain data obtained by two-dimensional turbo spectroscopic imaging (2DTSI) from patients affected by glioblastoma. The purpose of this study is to investigate the applicability of CCA when typing tissues of heterogeneous tumors. The performance of CCA is also compared with that of ordinary correlation analysis on s…
A new 8-oxo-7,8-2 ' deoxyguanosine nanoporous anodic alumina aptasensor for colorectal cancer diagnosis in blood and urine
Many important human diseases, and especially cancer, have been related to the overproduction of 8-oxo-7,8-dihydro-2 '-deoxyguanosine (8-oxo-dG). This molecule is a product of oxidative stress processes over nucleophilic bases in DNA. In this work, an aptasensor for the rapid, selective and accurate detection of this oncomarker is presented. The aptasensor consists of a nanoporous anodic alumina material loaded with a dye and is functionalized with an aptamer-based "molecular gate". In the presence of target 8-oxo-dG, the capping aptamer displaces from the surface due to the high affinity of the analyte with the capping aptamer, thus inducing delivery of the preloaded fluorescent dye. In co…
Urinary Metabolic Signatures Detect Recurrences in Non-Muscle Invasive Bladder Cancer
Patients with non-muscle invasive bladder cancer (NMIBC) undergo lifelong monitoring based on repeated cystoscopy and urinary cytology due to the high recurrence rate of this tumor. Nevertheless, these techniques have some drawbacks, namely, low accuracy in detection of low-grade tumors, omission of pre-neoplastic lesions and carcinomas in situ (CIS), invasiveness, and high costs. This work aims to identify a urinary metabolomic signature of recurrence by proton Nuclear Magnetic Resonance (1H NMR) spectroscopy for the follow-up of NMIBC patients. To do this, changes in the urinary metabolome before and after transurethral resection (TUR) of tumors are analyzed and a Partial Least Square Dis…
Metabolite identification in human liver needle biopsies by high-resolution magic angle spinning1H NMR spectroscopy
High-resolution magic angle spinning (HR-MAS) 1 H NMR spectroscopy of intact human liver needle biopsies has not been previously reported. HR-MAS NMR spectra collected on 17 specimens with tissue amounts between � 0.5 and 12 mg showed very good spectral resolution and signal-to-noise ratios. One-dimensional 1 H spectra revealed many intense signals corresponding to cellular metabolites. In addition, some high molecular weight metabolites, such as glycogen and mobile fatty acids, could be observed in some spectra. Resonance assignments for 22 metabolites were obtained by combining the analysis of three different types of 1D 1 H spectral editing, such as T2 filtering or the nuclear Overhauser…
Incremental Gaussian Discriminant Analysis based on Graybill and Deal weighted combination of estimators for brain tumour diagnosis
In the last decade, machine learning (ML) techniques have been used for developing classifiers for automatic brain tumour diagnosis. However, the development of these ML models rely on a unique training set and learning stops once this set has been processed. Training these classifiers requires a representative amount of data, but the gathering, preprocess, and validation of samples is expensive and time-consuming. Therefore, for a classical, non-incremental approach to ML, it is necessary to wait long enough to collect all the required data. In contrast, an incremental learning approach may allow us to build an initial classifier with a smaller number of samples and update it incrementally…
Strategies for annotation and curation of translational databases: the eTUMOUR project
Altres ajuts: LSHC/CT2004-503094 The eTUMOUR (eT) multi-centre project gathered in vivo and ex vivo magnetic resonance (MR) data, as well as transcriptomic and clinical information from brain tumour patients, with the purpose of improving the diagnostic and prognostic evaluation of future patients. In order to carry this out, among other work, a database-the eTDB-was developed. In addition to complex permission rules and software and management quality control (QC), it was necessary to develop anonymization, processing and data visualization tools for the data uploaded. It was also necessary to develop sophisticated curation strategies that involved on one hand, dedicated fields for QC-gene…
Magnetic Resonance Microscopy Contribution to Interpret High-Resolution Magic Angle Spinning Metabolomic Data of Human Tumor Tissue
[EN] HRMAS NMR is considered a valuable technique to obtain detailed metabolic profile of unprocessed tissues. To properly interpret the HRMAS metabolomic results, detailed information of the actual state of the sample inside the rotor is needed. MRM (Magnetic Resonance Microscopy) was applied for obtaining structural and spatially localized metabolic information of the samples inside the HRMAS rotors. The tissue was observed stuck to the rotor wall under the effect of HRMAS spinning. MRM spectroscopy showed a transference of metabolites from the tissue to the medium. The sample shape and the metabolite transfer after HRMAS indicated that tissue had undergone alterations and it can not be s…
Quantifying brain tumor tissue abundance in HR-MAS spectra using non-negative blind source separation techniques
Given high-resolution magic angle spinning (HR-MAS) spectra from several glial tumor subjects, our goal is to differentiate between tumor tissue types by separating the different sources that contribute to the profile of each spectrum. Blind source separation techniques are applied for obtaining characteristic profiles for necrosis, highly cellular tumor and border tumor tissue and providing the contribution (abundance) of each of these tumor tissue types to the profile of each spectrum. The problem is formulated as a non-negative source separation problem. Non-negative matrix factorization, convex analysis of non-negative sources and non-negative independent component analysis methods are …
Spectroscopic axonal damage of the right locus coeruleus relates to selective attention impairment in early stage relapsing-remitting multiple sclerosis
Summary Lower levels of N-acetylaspartate (NAA), a marker of axonal damage, have been found in the normal-appearing white matter (NAWM) of relapsing-remitting multiple sclerosis (RRMS) patients with low physical disability. However, its relation to the clinical status of these patients remains unclear. We explored the association between NAA levels [normalized to creatine (Cr), NAA/Cr] and a cognitive feature that is not measured by the standard scales that address functional disability [e.g. Expanded Disability Scale Score (EDSS)] in early RRMS. Given that a considerable number of RRMS patients present attentional dysfunction early in the disease and assuming a functional-anatomical orient…
Multiproject–multicenter evaluation of automatic brain tumor classification by magnetic resonance spectroscopy
[EN] Automatic brain tumor classification by MRS has been under development for more than a decade. Nonetheless, to our knowledge, there are no published evaluations of predictive models with unseen cases that are subsequently acquired in different centers. The multicenter eTUMOUR project (2004-2009), which builds upon previous expertise from the INTERPRET project (2000-2002) has allowed such an evaluation to take place. A total of 253 pairwise classifiers for glioblastoma, meningioma, metastasis, and low-grade glial diagnosis were inferred based on 211 SV short TE INTERPRET MR spectra obtained at 1.5 T (PRESS or STEAM, 20-32 ms) and automatically pre-processed. Afterwards, the classifiers …
A gated material as immunosensor for in-tissue detection of IDH1-R132H mutation in gliomas
[EN] A nanodevice consisted on nanoporous anodic alumina (NAA) supports functionalized with specific and selective antibody-based gatekeepers for the detection of IDH1-R132H mutant enzyme is here reported. Molecular profile and tissue mutations of the tumours (such as IDH1/IDH2 mutations in gliomas) are a great source of information that already make a difference in terms of prognosis and prediction of response to combined therapy. However, standardized methodologies to determine this mutation are time-consuming and cannot provide information before or during surgical intervention, which significantly limits their utility in terms of intraoperative decisionmaking. To solve this limitation, …
Determination of metabolite concentrations in human brain tumour biopsy samples using HR-MAS and ERETIC measurements.
Accurate determination of the concentration of the metabolites contained in intact human biopsies of 10 glioblastoma multiforme samples was achieved using one-dimensional 1H high-resolution magic angle spinning (HR-MAS) NMR combined with ERETIC™ (electronic reference to in vivo concentrations) measurements. The amount of sample used ranged from 6.8 to 12.9 mg. Metabolite concentrations were measured in each sample using two methods: with DSS (2,2-dimethyl-2-silapentane-5-sulfonate sodium salt) as an internal reference and with ERETIC™ as an external electronically generated reference. The ERETIC™ signal was shown to be highly reproducible and did not affect the spectral quality. The concent…