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Detection of Prostate Cancer using Voltammetric Electronic Tongue
Abstract
A simple method based on multivariate analysis of data from urine using an electronic voltammetric tongue is used to detect patients with prostate cancer. A sensitivity of 91% and a specificity of 73% was obtained to distinguish urine from cancer patients and urine from non cancer patients.
... integrate a system of non-specific sensors whose response can be analysed with a pattern recognition algorithm or multivariate analysis (Winquist, 2008), presenting remarkable capabilities for classification and quantification of physicochemical parameters. Application examples range from quality assessment in food (Cetó et al., 2016;Peris and Escuder-Gilabert, 2016;Tan and Xu, 2020) water (Cetó et al., 2016), environmental studies (Cetó and Valle, 2022) to pharmaceutics (Wasilewski et al., 2019) and biomedicine (Belugina et al., 2021;Braz et al., 2022;Lvova et al., 2009;Pascual et al., 2016;Solovieva et al., 2019) among others. ...
... A sensitivity and specificity >90% for the discrimination of PCa and healthy controls was obtained by Solovieva et al. with a potentiometric e-tongue in a set of 89 urines (Solovieva et al., 2019). VET has shown also a high sensitivity (91%) and specificity (73%) for the diagnosis of PCa in a set of 114 urines of patients with PCa and healthy controls, and are also promising for the application of this tool in the BC field (Pascual et al., 2016). Nevertheless, the context in the study of PCa and BC are different. ...
... Also deserves to be mentioned the fact that the set up here presented enables the study of this reduced volume without any dilution, which improves the results of this technique. Finally, the Ni working electrode has been here demonstrated to be important in the discriminant model, which was not used previously in the study of PCa by VET (Pascual et al., 2016). ...
Bladder cancer (BC) is the sixth leading cause of death by cancer. Depending on the invasiveness of tumours, BC patients will undergo surgery and surveillance lifelong, owing the high rate of recurrence and progression. In this context, the development of strategies to support non-invasive BC diagnosis is focusing attention. Voltammetric electronic tongue (VET) has been demonstrated to be of use in the analysis of biofluids. Here we present the implementation of a VET to study 207 urines to discriminate BC and non-BC for diagnosis and surveillance to detect recurrences. Special attention has been paid to the experimental setup to improve reproducibility in the measurements. PLSDA analysis together with variable selection provided a model with high sensitivity, specificity and area under the ROC curve AUC (0.844, 0.882 and 0.917 respectively). These results pave the way for the development of non-invasive low-cost and easy-to-use strategies to support BC diagnosis and follow-up.
... This system has been used to measure different biological samples (urine, exudates collected from cutaneous ulcers) with promising results. VA can detect levels of uremic toxins 5 , urinary creatinine and the severity of renal insufficiency; it also allows to discriminate urine of healthy subjects from urine of patients with benign or malignant bladder 6 and prostate tumors 7 . Furthermore, it has been confirmed that VA is a powerful technique to diagnose UTI 8 . ...
... It is likely that retesting it in a pure and larger population of spontaneous effusions would disclose better clinimetric properties. Secondly, we performed the voltammetric analysis according to the methods previously developed for the diagnosis of skin and bladder infections [5][6][7][8][9] . However, this might not be the best option for identifying a neoplastic pleural effusion. ...
Pleural effusion is very common, but an etiologic diagnosis is often difficult. We used three unconventional diagnostic techniques (voltammetric analysis, protein electrophoresis and pH measurement) performed on pleural effusion to do a preliminary distinction between a neoplastic and a non-neoplastic origin. Pleural fluid samples were collected through thoracentesis, thoracoscopy, or post-surgery pleural drainage of 116 patients admitted to acute care wards. Samples were analyzed with the three unconventional techniques: voltammetric analysis using the BIONOTE system, capillary electrophoresis and pH measurement using a potentiometric method. The BIONOTE system is an innovative system that performs a cyclic voltammetric analysis of a biological liquid sample. The final output of the electrochemical analysis is an electrical pattern that represents a fingerprint of the analyzed sample and each sample has a different fingerprint. Data from the three unconventional diagnostic techniques were analyzed using partial least squares discriminant analysis to discriminate neoplastic from non-neoplastic effusions; we also evaluated sensitivity, specificity and percentage of correct classification. The mean age was 68 years (SD: 12); 78 (67.24%) participants were men. Results obtained from all the unconventional techniques employed showed that neoplastic and non-neoplastic pleural effusions were correctly classified in 80.2% of cases, with a sensitivity of 77% and specificity of 83%. The combined use of voltammetric analysis, protein electrophoresis and pH measurement of pleural fluid can easily and quickly distinguish a neoplastic from a non-neoplastic pleural effusion with reliable accuracy and represents an innovative diagnostic approach. In fact, this protocol can be executed in just few minutes directly in the patient's bed and it holds great promise to improve the prognosis and therapeutic chances.
... In addition, due to the versatility of electronic tongues (ETs), they can be applied in different sectors. Therefore, some studies have shown that the largest applications are focused on water analysis (microorganisms, heavy metals, quality, nutrients, etc.) [65], agricultural analysis (evaluation of inorganic ions, soil type and fertility, pesticides) [105], medical analysis by studying blood, urine, tears, sweat, and saliva, which are important biological fluids that provide information about possible health problems of a patient (cancer, urinary diseases, creatinine levels, urea, etc.) [106][107][108], and food quality (microorganisms, mycotoxins, maturity, acidity, heavy metals, pesticides) [71,109,110]. ...
This study highlights the implementation of an electronic tongue composed of carbon screen-printed electrodes, which were used to discriminate and classify pesticides, such as Curathane, Numetrin, and Nativo in water. Therefore, to verify the capacity and performance of the sensory system, solutions of each of the pesticides at a concentration of 10 ppm were prepared in the laboratory and compared with distilled water. Furthermore, to evaluate the minimum detection limit of the electronic tongue, solutions were prepared at different concentrations: 0.02, 0.04, 0.06, 0.08, 0.1, 0.15, 0.2, and 0.25 ppm, respectively. The analysis and classification of the different categories and concentrations were obtained from the use of pattern recognition and automatic learning methods, such as principal component analysis (PCA), linear discriminant analysis (LDA), support vector machine (SVM), k-nearest neighbors (kNN), and naïve Bayes, during this process; the techniques accomplished more than 90% accuracy in pesticide concentrations. Finally, a 100% success rate in classifying the compound types was completely achieved.
... In another study, PLS-DA was employed for the classication of urine samples from 22 prostate cancer and 15 non-cancer patients using the multivariate electrochemical proles measured on a 7-electrode electronic voltammetric tongue, achieving 91% sensitivity and 73% specicity. 116 The aforementioned examples thus illustrate the ability of PLS algorithms to construct accurate classication or regression models from multivariate datasets, which portray distinct linear trends or separations. ...
Speedy, point-of-need detection and monitoring of small-molecule metabolites are vital across diverse applications ranging from biomedicine to agri-food and environmental surveillance. Nanomaterial-based sensor (nanosensor) platforms are rapidly emerging as excellent candidates for versatile and ultrasensitive detection owing to their highly configurable optical, electrical and electrochemical properties, fast readout, as well as portability and ease of use. To translate nanosensor technologies for real-world applications, key challenges to overcome include ultralow analyte concentration down to ppb or nM levels, complex sample matrices with numerous interfering species, difficulty in differentiating isomers and structural analogues, as well as complex, multidimensional datasets of high sample variability. In this Perspective, we focus on contemporary and emerging strategies to address the aforementioned challenges and enhance nanosensor detection performance in terms of sensitivity, selectivity and multiplexing capability. We outline 3 main concepts: (1) customization of designer nanosensor platform configurations via chemical-and physical-based modification strategies, (2) development of hybrid techniques including multimodal and hyphenated techniques, and (3) synergistic use of machine learning such as clustering, classification and regression algorithms for data exploration and predictions. These concepts can be further integrated as multifaceted strategies to further boost nanosensor performances. Finally, we present a critical outlook that explores future opportunities toward the design of next-generation nanosensor platforms for rapid, point-of-need detection of various small-molecule metabolites.
... Comparando los resultados obtenidos en este proyecto (los del modelo clasificador ensemble basado en SVM sin variables adicionales) con los resultados obtenidos por Loras et al. (2016) [7], se ha obtenido una menor sensibilidad (76.4% contra 86.4%) y especificidad (77.5% contra 80.9%), no batiendo los resultados obtenidos mediante espectroscopia de RMN. La ventaja de la lengua electrónica voltamétrica, pese a su menor poder de clasificación, es su capacidad de medición in situ e instantánea, de forma económica y sencilla (sin necesidad de personal altamente cualificado), características que no comparte con la espectroscopia de RMN, por lo que puede ser utilizada como método de cribado o screening, para posteriormente utilizar otras técnicas más sofisticadas, más invasivas o con mayor sensibilidad y especificidad. ...
The bladder cancer early detection is nowadays done through urine analysis of metabolites. This technique offers high specificity (>90%) but with moderate sensibility (<50%), and presents a temporal and economic cost related with the need of laboratory analysis. A candidate for replacing this technique is the use of an electronic tongue, which has given positive results for the prostate cancer early detection application. The electronic tongue would allow obtaining immediate results with practically any variable cost. In this project is developed and combined different classifying algorithms based on the measurements realized at La Fe Polytechnic Hospital through FraPlusMini equipment, an electronic tongue developed by IDM, at the same time that it is performed an analysis to improve the device for the application. Focused in these objectives multivariate analysis, data mining and neural networks are combined.
... Although urine commonly contains a mixture of low molecular mass and even volatile compounds, which can be detected by the senses (interestingly, also by using trained dogs) [82] or using a low-cost array of different electrodes (Ir, Rh, Pt, Au, Ag, Co and Cu, d = 2 mm)-so-called voltammetric electronic tongue (sensitivity 91% and a specificity 73% to detect PCa individuals) [83], the specific detection of a PCa biomarker is usually achieved by using a bioreceptive element. Citrate is an important part of a prostatic fluid, being produced by prostate cells with its level being affected directly by intracellular Zn concentration. ...
The review initially provides a short introduction to prostate cancer (PCa) incidence, mortality, and diagnostics. Next, the need for novel biomarkers for PCa diagnostics is briefly discussed. The core of the review provides details about PCa aetiology, alternative biomarkers available for PCa diagnostics besides prostate specific antigen and their biosensing. In particular, low molecular mass biomolecules (ions and metabolites) and high molecular mass biomolecules (proteins, RNA, DNA, glycoproteins, enzymes) are discussed, along with clinical performance parameters.
... Compared to the human gustatory system, the e-tongue is able to detect compounds far below the human threshold in complex matrices (Riul et al., 2003c;Riul et al., 2010;Jiang et al., 2018). In addition, to taste analyses (Riul et al., 2002(Riul et al., , 2003aManzoli et al., 2014;Daikuzono et al., 2015), the e-tongue also enables the analysis of inedible media and unpleasant formulations (Riul et al., 2010;Kirsanov et al., 2019), such as biological samples (Ciosek et al., 2008;Heras et al., 2010;Ha et al., 2015;Pascual et al., 2016), pollutants (Mimendia et al., 2010;Campos et al., 2012;Magro et al., 2019;Tazi et al., 2020), hazardous and toxic analytes (Kirsanov et al., 2013;Agir and Kundu, 2016;Cruz et al., 2018;Shimizu et al., 2019), pharmaceutics (Woertz et al., 2011a, b;Choi et al., 2014;Wesoły et al., 2017;Krieser et al., 2020;Facure et al., 2020), etc. To attend the desired characteristics and a high performance, the architecture of the sensing units, namely the materials employed in the composition of the e-tongue, must be accurately chosen (Vlasov et al., 2008;Riul et al., 2010;Ha et al., 2015). ...
In this book chapter we review recent advances on the use of electrospun and solution-blow spun nanofibers, which display remarkable features as high surface area to volume ratio, high porosity, mechanical flexibility and possibility of functionalization, in the design of chemoresistive, electrochemical, opto-chemical and electronic-tongue sensors. Emphasizes is given on the fabrication of nanofibers of varied size, shape as well as with distinct surface and bulk functionalization with active compounds to interact with analytes ranging from heavy metals, food contaminants, microorganism, volatile organic compounds, among others. Finally, future trends for nanofibers fabrication and application in sensors are also discussed.
... A voltammetric MSS comprising seven working electrodes (Ir, Rh, Pt, Au, Ag, Co, and Cu) versus saturated calomel reference electrodes was applied to detect patients with prostate cancer (PCa) [64]. The sample set comprised 114 samples: 71 samples from the patients with PCa before surgical treatment and 43 controls (26 from patients who underwent the surgery and 17 from individuals with benign prostatic hyperplasia). ...
“Electronic tongues”, “taste sensors”, and similar devices (further named as “multisensor systems”, or MSS) have been studied and applied mostly for the analysis of edible analytes. This is not surprising, since the MSS development was sometimes inspired by the mainstream idea that they could substitute human gustatory tests. However, the basic principle behind multisensor systems—a combination of an array of cross-sensitive chemical sensors for liquid analysis and a machine learning engine for multivariate data processing—does not imply any limitations on the application of such systems for the analysis of inedible media. This review deals with the numerous MSS applications for the analysis of inedible analytes, among other things, for agricultural and medical purposes.
... Voltammetry was also employed as a platform for recognition in medicine. The report [22] was exploring the potential of the voltammetric multisensor system in distinguishing urine samples from the patients with PCa and control group. Using 114 urine samples (71 with PCa and 43 control) and partial least squaresdiscriminant analysis the authors achieved sensitivity and specificity of 91% and 73%, correspondingly, however only one classification technique was employed (PLS-DA). ...
We report a simple potentiometric multisensor system for distinguishing the urine samples from the patients with diagnosed prostate cancer and from healthy control group. The sensors of the system are sensitive towards variety of cationic and anionic species in urine, as well as to the presence of RedOx pairs. The response of the system represents a complex chemical fingerprint of urine sample that can be related with patient status through multivariate modelling. 89 urine samples were studied (43 from cancer patients confirmed by prostatic puncture biopsy and 46 from healthy control group) and variety of multivariate classification techniques was applied to the potentiometric data. The best results were obtained with logistic regression model yielding 100% sensitivity and 93% specificity in the independent test set of samples.
Electronic tongue systems have been broadly employed in monitoring of food, beverage, and environment, forensics, cosmetics, pharmaceutical analysis, and medical diagnosis. This is because e-tongues can nearly discriminate samples of high complexity, reduce interference of the matrix, offer rapid response, non-destructive, miniaturization and on-site capabilities, compared to other analytical approaches that require expensive instrumentation, complex sample preparation and highly-skilled personnel. Even though electronic tongues are successfully commercialized, their application in cancer diagnosis from urine samples is underestimated. In this review, we would like to highlight the various analytical techniques such as Raman spectroscopy, infrared spectroscopy, fluorescence spectroscopy, and electrochemical techniques (potentiometry and voltammetry) used as e-tongues for urine analysis towards non-invasive cancer diagnosis. Besides, different machine learning approaches, for instance, supervised and unsupervised learning and algorithms are introduced to analyze extracted chemical data and to highlight the diagnostic capabilities of e-tongues in distinguishing between patients diagnosed with cancer and healthy controls.
The diagnosis of cancer and other diseases using data from non-specific sensors – such as the electronic tongues (e-tongues) - is challenging owing to the lack of selectivity, in addition to the variability of biological samples. In this study, we demonstrate that impedance data obtained with an e-tongue in saliva samples can be used to diagnose cancer in the mouth. Data taken with a single-response microfluidic e-tongue applied to the saliva of 27 individuals were treated with multidimensional projection techniques and non-supervised and supervised machine learning algorithms. The distinction between healthy individuals and patients with cancer on the floor of mouth or oral cavity could only be made with supervised learning. Accuracy above 80% was obtained for the binary classification (YES or NO for cancer) using a support vector machine (SVM) with radial basis function kernel and random forests. In the classification considering the type of cancer, the accuracy dropped to ca. 70%. The accuracy tended to increase when clinical information such as alcohol consumption was used in conjunction with the e-tongue data. With the random forest algorithm, the rules to explain the diagnosis could be identified using the concept of multidimensional calibration space. Since the training of the machine learning algorithms is believed to be more efficient when the data of a larger number of patients are employed, the approach presented here is promising for computer-assisted diagnosis.
This book provides information about different types and stages of cancer and their subtypes with their respective molecular mechanisms, etiology, histopathology, and cellular origins. This book also provides detailed information about cancer incidence, mortality, and different types of technologies both bio and nano employed in cancer diagnosis and screening, and their applications in cancer therapies. This book informs readers about molecular mechanisms of cancer, diagnosis, and therapies along with different computational techniques used on a single platform. The chapters include a broad and integrated perspective on cancer-related topics. This book covers both conventional and emerging techniques employed in cancer screening and diagnosis, including imaging, biomarker, and electrochemical nanosensor-based approaches with detailed information on sensor development. Similarly, this book also covers the mechanisms of different conventional and emerging herbal and nano therapies used in cancer treatment. The authors discuss applications of different computational and mathematical tools, such as machine-learning methods, that can be employed in cancer diagnosis and therapy at the level of personalized medicine. Features: Offers an integrated approach to provide information about all aspects of cancer biology, diagnosis, and therapy Focuses on both conventional and emerging tools/techniques applicable in cancer screening and diagnosis Covers the mechanisms of conventional and emerging anticancer drugs and therapies Provides insights about a personalized medicine-based approach in cancer diagnosis and therapy. This book is essential for university students, course lecturers, researchers, and industrialists working in the fields of cancer biology, medicine, and pharmacology.
The main reason to resort to electronic tongues arises in situations where the use of a human panel is not possible, such as in the continuous monitoring of industrial processes, analysis of unpleasant or poisonous/hazardous samples (drugs, virus, bacteria, pollutants), and for economical limitations. This chapter describes recent advances with special emphasis on microfluidic platforms based on polymers and paper, new designs, and new sensing and biosensing applications. The use of electroactive species to provide high specificity in pharmaceuticals enabled the e‐tongue application to detect atenolol and propranolol, insulin, diclofenac, and amino acids. Bio e‐tongues have been used in water analysis; to discriminate varieties of grapes through phenolic and sugar content; to detect phytic acid; for the diagnosis of Chagas and Leishmaniasis diseases; and to detect catechol, glucose, and triglycerides. Microfluidic systems appeared after C.M. Daikuzono et al. proved the successful usage of the first microfluidic e‐tongue design.
Voltammetric electronic tongue (VE-tongue) is a promising technology for advanced sensing and measurement applications. The review examines the measurement principles, working parameters and configurations of different types of voltammetric electronic tongues (VE-tongue): the VE-tongue based on bare electrodes, modified electrodes and biosensors. The working parameters of these VE-tongues (electrode cleaning method, pulsed voltammetry and pre-processing of responses data) are described, and the development of VE-tongue based on miniaturized sensors arrays and automatic flow techniques is also presented. The applications of foodstuff analysis commented include recognition of basic tastes substances, tracing origins/samples recognition, process monitoring, and quality investigation. Finally, the unsolved problems and significant efforts of VE-tongues are depicted.
Prostate cancer (PCa) is the most frequent noncutaneous malignancy in the male population. Although prostate specific antigen (PSA) blood testing remains the most widely used tool for PCa detection, this suffers from a number of problems. In the particular case of PCa, metabolites for PCa detection have been measured using a large variety of techniques in a range of different samples including tissue extracts, prostatic fluid and serum. Although these studies have increased the biological understanding of PCa, they do not provide a holistic picture of the malignant status. Additionally, most of these studies have been reported in prostate tissues extracts and, indeed it is apparent from the literature that studies on body fluids, especially urine, in relation to PCa are very rare. However, the potential use of simple urine samples to detect PCa is highly appealing as urine is collected non-invasively and requires minimal sample preparation prior to analysis. Based on these concepts, we focused our attention on the potential use of urine as suitable fluid and 1H NMR as an easy technique for PCa detection. The aim of this work was to assess the prospective use of 1H NMR spectra profiles of urine samples combined with multivariate analysis as a simple diagnostic tool for the potential correct classification of patients with PCa. In particular 113 urine samples were used and split into calibration and validation subsets. In the validation set the model correctly classifies 36 samples out of 50 for patients with PCa, and 14 samples out of 14 correctly from control patients. In a wider context, given the relatively low cost and easy of 1H NMR and the expected parallel advances being made in magnetic resonance equipment and in the automatization of multivariate statistical analysis, we believe that this simple approach of using 1H NMR profiles of urine as “fingerprints” has great potential for applications in the detection of certain clinically significant diseases (i.e. PCa) and for combining diagnosis and further simple monitoring after therapy.
Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.
Prostate cancer (PCa) is the most commonly diagnosed visceral cancer in men and is responsible for the second highest cancer-related male mortality rate in Western countries, with increasing rates being reported in Korea, Japan, and China. Considering the low sensitivity of prostate-specific antigen (PSA) testing, it is widely agreed that reliable, age-independent markers of the presence, nature, and progression of PCa are required to facilitate diagnosis and timely treatment. Metabolomics or metabonomics has recently emerged as a novel method of PCa detection owing to its ability to monitor changes in the metabolic signature, within biofluids or tissue, that reflect changes in phenotype and function. This review outlines the physiology of prostate tissue and prostatic fluid in health and in malignancy in relation to metabolomics as well as the principles underlying the methods of metabolomic quantification. Promising metabolites, metabolic profiles, and their correlation with the presence and stage of PCa are summarized. Application of metabolomics to biofluids and in vivo quantification as well as the direction of current research in supplementing and improving current methods of detection are discussed. The current debate in the urology literature on sarcosine as a potential biomarker for PCa is reviewed and discussed. Metabolomics promises to be a valuable tool in the early detection of PCa that may enable earlier treatment and improved clinical outcomes.
Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.
In the post-genomic era, several profiling tools have been developed to provide a more comprehensive picture of tumour development and progression. The global analysis of metabolites, such as by mass spectrometry and high-resolution 1H nuclear magnetic resonance spectroscopy, can be used to define the metabolic phenotype of cells, tissues or organisms. These 'metabolomic' approaches are providing important information about tumorigenesis, revealing new therapeutic targets and will be an important component of automated diagnosis.
The genetic and molecular mechanisms responsible for and associated specifically with the development and progression of malignant prostate cells are largely unidentified. In addition, despite its implication in virtually all malignant cells, the role of altered cellular metabolism as an essential factor in prostate malignancy has been largely ignored. Moreover, the intermediary metabolism of normal prostate as well as malignant prostate cells is among the least studied and most poorly understood of all mammalian cells. Some important factors, especially the role of zinc, have been identified and implicated in the development and progression of prostate malignancy. In this review, we provide a current and updated integrated assessment of the relationships of intermediary metabolism in normal prostate and in prostate cancer. The experimental and clinical evidence that leads to the formulation of concepts of normal and malignant prostate metabolism is presented. The evidence for a concept of zinc as a tumor suppressor agent and Zip1 zinc transporter as a tumor-suppressor gene is described.
The specialized function of the normal prostate glandular epithelium to produce and secrete enormously high levels of citrate involves and requires unique intermediary metabolism activities that are not generally associated with other normal mammalian cells. The accumulation of zinc by these cells is an essential factor in this unique metabolic relationship. In malignancy, the normal zinc-accumulating citrate-producing epithelial cells are metabolically transformed to citrate-oxidizing cells that lose the ability to accumulate zinc. A genetic alteration in the expression of ZIP1 zinc transporter is associated with this metabolic transformation. These genetic/metabolic relationships have important consequences on citrate-related metabolism, bioenergetics, cell proliferation and invasive capabilities of the malignant cells, which result in tumor-suppression characteristics.
The genetic/metabolic relationships in normal prostate glandular epithelium are driven by the unique function to accumulate and secrete citrate. The genetic/metabolic transformation of the prostate malignant cells is driven by the metabolic/bioenergetic, growth/proliferative, and invasive/migration requirements of the malignant process. Zinc is critical to these relationships. An understanding of these genetic/metabolic relationships provides new directions and opportunities for development of regimens for the prevention and treatment of prostate cancer. Important insight into the genetic/metabolic requirements of the prostate malignant process is now evolving. Most importantly at this time, an appreciation and recognition of the genetic/metabolic significance and implications in the development of prostate malignancy is imperative; and much needed research in this area is essential. Hopefully, this review will help to achieve these goals.
Prostate volume correlates both with prostate-specific antigen (PSA) values and with the presence of benign prostatic hyperplasia (BPH). Here we examine the relationship between prostate volume and PSA level in a large, geographically diverse sample of men undergoing prostate cancer screening.
We followed 35,323 men enrolled in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Each man was screened with digital rectal examination (DRE) and PSA levels for up to 4 years. Prostate volume was estimated by DRE performed by trained examiners at the PLCO sites. Linear and logistic regression was used to assess the effect of prostate volume and age on PSA levels. Regression coefficients were adjusted for the effect of prostate volume measurement error.
Prostate volume estimated by DRE showed considerable measurement error. Averaging volume over screening visits and accounting for examiner bias greatly reduced this error. Linear regression analysis showed a slope of 0.030/cm3 of log PSA on prostate volume when correcting for measurement error (95% confidence interval [CI], 0.029 to 0.031). Age was independently associated with (log) PSA, with a slope of 0.022 per year. Logistic regression analysis of the risk of having an elevated PSA value (exceeding 4 ng/mL) showed an odds ratio of 1.9 (95% CI, 1.8 to 2.0) associated with a 10 cm3 increase in prostate volume. The correlation of log PSA and prostate volume was 0.37. Prostate volume was not correlated with body mass index and showed weak correlation (r = 0.14) with age.
Prostate volume and age are independently associated with increased PSA levels in a population of men undergoing screening.
Early detection of prostate cancer is associated with the diagnosis of a considerable proportion of cancers that are indolent, and that will hardly ever become symptomatic during lifetime. Such overdiagnosis should be avoided in all forms of screening because of potential adverse psychological and somatic side effects. The main threat of overdiagnosis is overtreatment of indolent disease. Men with prostate cancer that is likely to be indolent may be offered active surveillance. Evaluation of active surveillance studies and validation of new biological parameters for risk assessment are expected.
In (1) H MR spectroscopic imaging ((1) H-MRSI) of the prostate the spatial distribution of the signal levels of the metabolites choline, creatine, polyamines, and citrate are assessed. The ratio of choline (plus spermine as the main polyamine) plus creatine over citrate [(Cho+(Spm+)Cr)/Cit] is derived from these metabolites and is used as a marker for the presence of prostate cancer. In this review, the factors that are of importance for the metabolite ratio are discussed. This is relevant, because the appearance of the metabolites in the spectrum depends not only on the underlying anatomy, metabolism, and physiology of the tissue, but also on acquisition parameters. These parameters influence especially the spectral shapes of citrate and spermine resonances, and consequently, the (Cho+(Spm+)Cr)/Cit ratio. Both qualitative and quantitative approaches can be used for the evaluation of (1) H-MRSI spectra of the prostate. For the quantitative approach, the (Cho+(Spm+)Cr)/Cit ratio can be determined by integration or by a fit based on model signals. Using the latter, the influence of the acquisition parameters on citrate can be taken into account. The strong overlap between the choline, creatine, and spermine resonances complicates fitting of the individual metabolites. This overlap and (unknown, possibly tissue-related) variations in T1, T2, and J-modulation hamper the application of corrections needed for a "normalized" (Cho+(Spm+)Cr)/Cit ratio that would enable comparison of spectra measured with different prostate MR spectroscopy protocols. Quantitative (Cho+(Spm+)Cr)/Cit thresholds for the evaluation of prostate cancer are therefore commonly established per institution or per protocol. However, if the same acquisition and postprocessing protocol were used, the ratio and the thresholds would be institution-independent, promoting the clinical usability of prostate (1) H-MRSI. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.
Metabolomic imaging of prostate cancer (PCa) aims to improve in vivo imaging capability so that PCa tumors can be localized noninvasively to guide biopsy and evaluated for aggressiveness prior to prostatectomy, as well as to assess and monitor PCa growth in patients with asymptomatic PCa newly diagnosed by biopsy. Metabolomics studies global variations of metabolites with which malignancy conditions can be evaluated by profiling the entire measurable metabolome, instead of focusing only on certain metabolites or isolated metabolic pathways. At present, PCa metabolomics is mainly studied by magnetic resonance spectroscopy (MRS) and mass spectrometry (MS). With MRS imaging, the anatomic image, obtained from magnetic resonance imaging, is mapped with values of disease condition-specific metabolomic profiles calculated from MRS of each location. For example, imaging of removed whole prostates has demonstrated the ability of metabolomic profiles to differentiate cancerous foci from histologically benign regions. Additionally, MS metabolomic imaging of prostate biopsies has uncovered metabolomic expression patterns that could discriminate between PCa and benign tissue. Metabolomic imaging offers the potential to identify cancer lesions to guide prostate biopsy and evaluate PCa aggressiveness noninvasively in vivo, or ex vivo to increase the power of pathology analysis. Potentially, this imaging ability could be applied not only to PCa, but also to different tissues and organs to evaluate other human malignancies and metabolic diseases.
Prostate cancer (PCa) is the most frequently diagnosed malignancy in men worldwide, largely as a result of the increased use of the annual serum prostate-specific antigen (PSA) screening test for detection. PSA screening has saved lives, but it has also resulted in the overtreatment of many patients with PCa because of a limited ability to accurately localize and characterize PCa lesions through imaging. High-resolution magic angle spinning (HRMAS) (1) H MRS has proven to be a strong potential clinical tool for PCa diagnosis and prognosis. The HRMAS technique allows valuable metabolic information to be obtained from ex vivo intact tissue samples and also enables the performance of histopathology on the same tissue specimens. Studies have found that the quantification of individual metabolite levels and metabolite ratios, as well as metabolomic profiles, shows strong potential to improve accuracy in PCa detection, diagnosis and monitoring. Ex vivo HRMAS is also a valuable tool for the interpretation of in vivo results, including the localization of tumors, and thus has the potential to improve in vivo diagnostic tests used in the clinic. Here, we primarily review publications of HRMAS (1) H MRS and its use for the study of intact human prostate tissue. Copyright © 2013 John Wiley & Sons, Ltd.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,660,290 new cancer cases and 580,350 cancer deaths are projected to occur in the United States in 2013. During the most recent 5 years for which there are data (2005-2009), delay-adjusted cancer incidence rates declined slightly in men (by 0.6% per year) and were stable in women, while cancer death rates decreased by 1.8% per year in men and by 1.5% per year in women. Overall, cancer death rates have declined 20% from their peak in 1991 (215.1 per 100,000 population) to 2009 (173.1 per 100,000 population). Death rates continue to decline for all 4 major cancer sites (lung, colorectum, breast, and prostate). Over the past 10 years of data (2000-2009), the largest annual declines in death rates were for chronic myeloid leukemia (8.4%), cancers of the stomach (3.1%) and colorectum (3.0%), and non-Hodgkin lymphoma (3.0%). The reduction in overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of approximately 1.18 million deaths from cancer, with 152,900 of these deaths averted in 2009 alone. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those groups in the lowest socioeconomic bracket and other underserved populations. CA Cancer J Clin 2013;. © 2013 American Cancer Society.
Purpose:
Prostate specific antigen and digital rectal examination have low specificity for detecting prostate cancer and they poorly predict the presence of aggressive disease. Urine is readily available and noninvasive, and it represents a promising source of biomarkers for the early detection and prediction of prostate cancer prognosis. We identified promising biomarkers for urine based prostate cancer, examined trends and outlined potential pitfalls.
Materials and methods:
We performed PubMed® and Web of Science® database searches of the peer reviewed literature on urine based testing for prostate cancer. Original studies of this subject as well as a small number of reviews were analyzed, including the strengths and weaknesses. We provide a comprehensive review of urine based testing for prostate cancer that covers the technical aspects, including the methodology of urine collection, as well as recent developments in biomarkers spanning the fields of genomics, epigenetics, transcriptomics, proteomics and metabolomics.
Results:
The process of urine collection is subject to variability, which may result in conflicting clinical results. Detecting prostate cancer in urine is technically feasible, as demonstrated by numerous proof of principle studies, but few markers have been validated in multiple large sample sets. Biomarker development using urine has been accelerating in recent years with numerous studies identifying DNA, RNA, protein and metabolite based biomarkers in urine. Advanced clinical studies have identified PCA3 and TMPRSS2:ERG fusion transcripts as promising RNA markers for cancer detection and possibly prognosis. DNA methylation analysis of multiple genes improves specificity and represents a promising platform for developing clinical grade assays.
Conclusions:
Urine based testing is noninvasive and represents a rich source of novel biomarkers for prostate cancer. Although urine shows promise for detecting cancer, the ability to identify aggressive subsets of prostate cancer needs further development.
The USPTSF bases its recommendation, in large part, on the 2 largest published randomized clinical trials (2). The U.S. PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial randomly assigned 76 685 men aged 55 to 74 years to receive either annual screening for 6 years or “usual care” (3). By 2009, 57% of the men had been followed for at least 13 years. The cumulative incidence rate for prostate cancer was slightly higher in the screened group, and prostate cancer mortality did not differ significantly between groups (3). The ERSPC (European Randomized Study of Screening for Prostate Cancer) randomly assigned 162 243 men aged 55 to 69 years to either PSA screening once every 4 years or an unscreened control group (4). After a median 11 years of follow-up, the cumulative incidence of prostate cancer was 8.2% in the screened group and 4.8% in the control group. Prostate cancer death was reduced by 21% in the screened group compared with the control group and 29% after adjustment for noncompliance (5). The Task Force concluded that this decrease in prostate cancer–specific mortality amounted to few lives saved and did not outweigh the harms of screening and diagnosis (false-positive results and associated anxiety and biopsy complications) and the harms related to the treatment of screen-detected cancer.
This review discusses basic principles and applications of voltammetric electronic tongues. It is introduced by a description
of the concept of electronic tongues or taste sensors followed by a general overview of electrochemical measurement principles
that have been used for electronic tongues. A special emphasis is given on measurement principles for voltammetric electronic
tongues, also including pulse voltammetry and variable reduction. Applications of voltammetric electronic tongue are described,
such as in the food industry, environmental analysis, paper and pulp industry, household appliances and agriculture. Future
developments of the concept, such as self polishing or miniaturized devices are also described. Finally, a continuous measurement
system for chemical oxygen demand (COD), which has been commercialized, is depicted.
The Electronic tongue (ET) composed of different kind of potentiometric chemical sensors has been applied for the detection of urinary system dysfunctions and creatinine levels. The creatinine contents evaluated by ET were compared with those obtained by automated Jaffe’s method and GC-MS, obtaining a satisfying agreement for both methods. Partial least square regression discriminate analysis (PLS-DA) and feed forward back-propagation neural network (FFBP NN) classified 51 urine specimens from healthy volunteers in four classes, according to the creatinine content, showing that both techniques can satisfactorily differentiate urines according to this parameter. The best accuracy result of 92.2% correct classification of unknown samples was achieved with FFBP NN. Moreover, the possibility of ET system to distinguish between urine samples of healthy patients, and those with malignant and non-malignant tumor diagnosis of bladder has been shown.
The prostate has long been known to exhibit unique metabolite profiles. In the last decade, advances in nuclear magnetic resonance spectroscopy and mass spectrometry have been applied toward identifying metabolic alterations in prostate cancer that may provide clinically useful biomarkers. As with genomics and proteomics, advances in technology and bioinformatics have led to the application of metabolomic profiling to prostate cancer-the high throughput evaluation of a large complement of metabolites in the prostate and how they are altered by disease perturbations. Recently, high profile publications have drawn attention to the potential of metabolomic analysis to identify biomarkers for early detection or disease progression from readily accessible body fluids as well as tissue specimens from biopsy and surgery. This review will examine applications of metabolomics to prostate cancer and highlight clinical associations and potential challenges.
Volatiles organic compounds (VOCs) in urine have been proposed as cancer biomarkers.
To evaluate the efficacy of prostate cancer (PCa) detection by trained dogs on human urine samples.
A Belgian Malinois shepherd was trained by the clicker training method (operant conditioning) to scent and recognize urine of people having PCa. All urine samples were frozen for preservation and heated to the same temperature for all tests. After a learning phase and a training period of 24 mo, the dog's ability to discriminate PCa and control urine was tested in a double-blind procedure. Urine was obtained from 66 patients referred to a urologist for elevated prostate-specific antigen or abnormal digital rectal examination. All patients underwent prostate biopsy and two groups were considered: 33 patients with cancer and 33 controls presenting negative biopsies.
During each "run," the dog was asked to signal a cancer urine among six samples containing only one cancer urine and five randomly selected controls. Sensitivity and specificity of the test were assessed.
The dog completed all the runs and correctly designated the cancer samples in 30 of 33 cases. Of the three cases wrongly classified as cancer, one patient was rebiopsied and a PCa was diagnosed. The sensitivity and specificity were both 91%.
This study shows that dogs can be trained to detect PCa by smelling urine with a significant success rate. It suggests that PCa gives an odor signature to urine. Identification of the VOCs involved could lead to a potentially useful screening tool for PCa.
This minireview describes the main developments of electronic tongues (e-tongues) and taste sensors in recent years, with a summary of the principles of detection and materials used in the sensing units. E-tongues are sensor arrays capable of distinguishing very similar liquids employing the concept of global selectivity, where the difference in the electrical response of different materials serves as a fingerprint for the analysed sample. They have been widely used for the analysis of wines, fruit juices, coffee, milk and beverages, in addition to the detection of trace amounts of impurities or pollutants in waters. Among the various principles of detection, electrochemical measurements and impedance spectroscopy are the most prominent. With regard to the materials for the sensing units, in most cases use is made of ultrathin films produced in a layer-by-layer fashion to yield higher sensitivity with the advantage of control of the film molecular architecture. The concept of e-tongues has been extended to biosensing by using sensing units capable of molecular recognition, as in films with immobilized antigens or enzymes with specific recognition for clinical diagnosis. Because the identification of samples is basically a classification task, there has been a trend to use artificial intelligence and information visualization methods to enhance the performance of e-tongues.
The prostate gland secretes many proteins in a prostatic fluid that combines with seminal vesicle derived fluids to promote sperm activation and function. Proximal fluids of the prostate that can be collected clinically are seminal plasma and expressed-prostatic secretion (EPS) fluids. EPS represents the fluid being secreted by the prostate following a digital rectal prostate massage, which in turn can be collected in voided urine post-exam. This collection is not disruptive to a standard urological exam, and it can be repeatedly collected from men across all prostatic disease states. A direct EPS fluid can also be collected under anesthesia prior to prostatectomy. While multiple genetic assays for prostate cancer detection are being developed for the shed epithelial cell fraction of EPS urines, the remaining fluid that contains many prostate-derived proteins has been minimally characterized. Approaches to optimization and standardization of EPS collection consistent with current urological exam and surgical practices are described, and initial proteomic and glycomic evaluations of the of EPS fluid are summarized for prostate specific antigen and prostatic acid phosphatase. Continued characterization of the prostate specific protein components of EPS urine combined with optimization of clinical collection procedures should facilitate discovery of new biomarkers for prostate cancer.
Non-invasive detection and prognostic evaluation of cancer represents a formidable challenge. Studies of the entire metabolite composition of cells promise advances towards this objective for prostate cancer.
Metabolomics, an omic science in systems biology, is the global quantitative assessment of endogenous metabolites within a biological system. Either individually or grouped as a metabolomic profile, detection of metabolites is carried out in cells, tissues, or biofluids by either nuclear magnetic resonance spectroscopy or mass spectrometry. There is potential for the metabolome to have a multitude of uses in oncology, including the early detection and diagnosis of cancer and as both a predictive and pharmacodynamic marker of drug effect. Despite this, there is lack of knowledge in the oncology community regarding metabolomics and confusion about its methodologic processes, technical challenges, and clinical applications. Metabolomics, when used as a translational research tool, can provide a link between the laboratory and clinic, particularly because metabolic and molecular imaging technologies, such as positron emission tomography and magnetic resonance spectroscopic imaging, enable the discrimination of metabolic markers noninvasively in vivo. Here, we review the current and potential applications of metabolomics, focusing on its use as a biomarker for cancer diagnosis, prognosis, and therapeutic evaluation.
Serum prostate specific antigen (PSA) levels were measured in 139 patients with benign prostatic hyperplasia (BPH) and in 88 patients with prostate cancer who were managed by deferred treatment. Acute urinary retention and large prostate glands tended to be associated with high PSA levels, but at levels greater than 10 ng/ml there was a significant risk of carcinoma being found on subsequent histological examination. The risk of progression of untreated prostate cancer was associated with levels of PSA greater than 20 ng/ml and with a high rate of change of PSA level. The value of measuring PSA in these patients is discussed.
The purpose of this study was to examine the diagnostic efficiency of prostate-specific antigen (PSA) and digital rectal examination (DRE) testing when using either 4.0 ng/ml or an age-specific reference range (ASRR) as an abnormal cutoff PSA value.
Between 1992-1995, 116,073 men, aged 40-79 years, were screened during Prostate Cancer Awareness Week. When using a 4.0-ng/ml cutoff PSA value, 22,014 had either an abnormal PSA, an abnormal DRE, or both. When using an ASRR cutoff PSA value, 17,561 had either an abnormal PSA, an abnormal DRE, or both. The positive predictive value (PPV), sensitivity, and specificity of PSA, DRE, and combined PSA and DRE tests were evaluated.
When using a 4.0-ng/ml cutoff PSA value, the PPVs of abnormal PSA alone, abnormal DRE alone, and combined abnormal PSA and DRE tests were 27.7%, 17.7%, and 56.0%, respectively. Sensitivities were 34.9%, 27.1%, and 38.0%, respectively. Specificities were 63.1%, 49.0%, and 87.9%, respectively. When using an ASRR cutoff PSA value, the PPVs of each category were 31.8%, 20.8%, and 63.7%, respectively. Sensitivities were 27.1%, 41.0%, and 31.8%, respectively. Specificities were 75.0%, 32.8%, and 92.2%, respectively. The PPVs of the PSA test were higher than those of the DRE. The PPVs of combined tests were highest when using either a 4.0-ng/ml cutoff PSA value or an ASRR cutoff PSA value (all P < 0.001). When using an ASRR, the PPVs of PSA, DRE, and combined tests were higher than those when using a 4.0-ng/ml without statistical significance (all P > 0.05). Sensitivity of PSA when using an ASRR was lower than when using 4.0 ng/ml.
Significantly higher PPVs indicated that utilizing both a PSA test and a DRE is most effective in screening for the early detection of prostate cancer. Although higher PPVs when using an ASRR cutoff PSA value suggested fewer unnecessary biopsies, lower sensitivities resulted in fewer cancers detected. Thus, we recommend that the combination of a PSA test with a cutoff value of 4.0 ng/ml and a DRE should continue to be utilized in the screening programs.
To retrospectively investigate the use of percent free prostate-specific antigen (PSA) compared with total PSA in serum as predictor of prostate cancer in men selected randomly from the general population who underwent biopsy on the basis of abnormal findings on digital rectal examination (DRE) or transrectal ultrasound (TRUS) and/or serum PSA levels greater than 10 ng/mL.
A single intervention, population-based screening study was undertaken in 1988 and 1989. Of the 2400 men aged 55 to 70 years invited to participate, 1782 men responded and were examined with DRE, TRUS, and PSA testing (Tandem-Hybritech). In 1995, frozen serum samples from 1748 men were analyzed for percent free PSA (Prostatus, Wallac OY). Five-year follow-up data on new cancers in the screened population were obtained from the Swedish Cancer Registry (SCR).
Of the 1748 men, 367 underwent TRUS-guided biopsies because of abnormal findings on either DRE or TRUS or serum PSA levels of greater than 10 ng/mL. This resulted in the diagnosis of 64 cases of prostate cancer (3.7%). PSA levels of 3.0 ng/mL or greater were found in 55 (86%) of 64 cancer cases and in 399 (24%) of the 1684 benign cases. Among the 1294 men with PSA less than 3.0 ng/mL, 9 prostate cancers were diagnosed (14% of all prostate cancers). All 9 patients with cancer and with PSA less than 3.0 ng/mL had a percent free PSA of 18% or less. In the group of 1109 patients with PSA less than 3.0 ng/mL and a percent free PSA greater than 18%, 159 biopsies were performed because of abnormal DRE or TRUS. However, no prostate cancer was diagnosed in this category of patients. Five years after the screening intervention, 7 more cases of prostate cancer were clinically diagnosed in the screened population according to the SCR.
The combination of PSA levels less than 3.0 ng/mL and percent free PSA greater than 18% defines a large part of the population at a very low risk of cancer of the prostate both at the time of screening and during the following 5 years. Men in this group may be spared DRE, and longer screening intervals may be considered. However, the risk of having prostate cancer is not negligible in men with PSA less than 3.0 ng/mL and percent free PSA of 18% or less. The results of this study indicate that biopsy should be recommended to men fulfilling these criteria, although these results should be confirmed in larger prospective studies because of the limited number of patients with prostate cancer in the present series.
At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish "redox homeostasis." Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman (J Gerontol 11: 298-300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
Diagnostic advancements for prostate cancer have so greatly increased early detections that hope abounds for improved patient outcomes. However, histopathology, which guides treatment, often subcategorizes aggressiveness insufficiently among moderately differentiated Gleason score (6 and 7) tumors (>70% of new cases). Here, we test the diagnostic capability of prostate metabolite profiles measured with intact tissue magnetic resonance spectroscopy and the sensitivity of local prostate metabolites in predicting prostate cancer status. Prostate tissue samples (n = 199) obtained from 82 prostate cancer patients after prostatectomy were analyzed with high-resolution magic angle spinning proton magnetic resonance spectroscopy, and afterwards with quantitative pathology. Metabolite profiles obtained from principal component analysis of magnetic resonance spectroscopy were correlated with pathologic quantitative findings by using linear regression analysis and evaluated against patient pathologic statuses by using ANOVA. Paired t tests show that tissue metabolite profiles can differentiate malignant from benign samples obtained from the same patient (P < 0.005) and correlate with patient serum prostate-specific antigen levels (P < 0.006). Furthermore, metabolite profiles obtained from histologically benign tissue samples of Gleason score 6 and 7 prostates can delineate a subset of less aggressive tumors (P < 0.008) and predict tumor perineural invasion within the subset (P < 0.03). These results indicate that magnetic resonance spectroscopy metabolite profiles of biopsy tissues may help direct treatment plans by assessing prostate cancer pathologic stage and aggressiveness, which at present can be histopathologically determined only after prostatectomy.
Urea biosensors based on urease covalently immobilized on to ammonium and hydrogen ion-selective electrodes were included in arrays together with ammonium, potassium, sodium, hydrogen and generic response to alkaline sensors. Response models based on artificial neural network (ANN) and partial least squares (PLS1) were built, tested and compared for the simultaneous determination of urea, ammonium, potassium and sodium. The results show that it is possible to obtain good ANN and PLS calibration models for simultaneous determination of these four species, but with better prediction capability when the ANN are used. The developed bioelectronic tongue was applied to multidetermination in urine samples. The ANN model showed again better agreement with reference methods, allowing a simple direct determination of urea in the real samples without the necessity of eliminating the alkaline interferences, or compensating endogenous ammonium.
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