Ανασκόπηση Πολυπαραμετρικών Συστημάτων Υποστήριξης Κλινικών Αποφάσεων για την Πρόγνωση και Κλινική Διαχείριση του Καρκίνου

Ο καρκίνος αποτελεί μάστιγα της εποχής μας, με τις στατιστικές να τον τοποθετούν ως τη δεύτερη αιτία θανάτου παγκοσμίως. Αν και η έγκαιρη ανίχνευση και διάγνωση αποτελούν τα σημαντικότερα βήματα για την αντιμετώπισή του, η πρόγνωση του καρκίνου παραμένει εξίσου σημαντική. Η πρόγνωση περιλαμβάνει την πρόβλεψη της πιθανότητας εμφάνισης καρκίνου, την πρόβλεψη υποτροπής των ασθενών και την πρόβλεψη επιβίωσης (προσδόκιμο ζωής). Τα παραπάνω αποτελέσαν αντικείμενο μελέτης σε πολλές δημοσιευμένες έρευνες τα τελευταία χρόνια. Οι συγγραφείς–ερευνητές επιχείρησαν, χρησιμοποιώντας μεθόδους μηχανικής μάθησης και αλγορίθμους ταξινόμησης, να αναπτύξουν ολοκληρωμένα συστήματα υποστήριξης αποφάσεων, τα οποία μπορούν να παράγουν μια πρόβλεψη για την κατάσταση ενός ασθενούς με ικανοποιητική, συνήθως, ακρίβεια. Η εν λόγω πρόβλεψη μπορεί να βοηθήσει τους θεράποντες ιατρούς στη λήψη αποφάσεων, εξατομικευμένων για κάθε ασθενή, καθιστώντας τα συστήματα υποστήριξης κλινικών αποφάσεων χρήσιμα κλινικά εργαλεία. Στην παρούσα διπλωματική εργασία, έγινε μια προσπάθεια να συγκεντρωθούν και να παρουσιαστούν μελέτες που περιλαμβάνουν τέτοιου είδους συστήματα για διαφορετικούς τύπους καρκίνου, να αξιολογηθούν τα αποτελέσματά τους και να εξαχθούν κάποια συμπεράσματα όσον αφορά τη δομή των συστημάτων υποστήριξης κλινικών αποφάσεων, τα δεδομένα που χρησιμοποιήθηκαν για τα σύνολα εκπαίδευσης και επαλήθευσης, τις τεχνικές ταξινόμησης και την απόδοσή τους. Για την πραγματοποίηση της έρευνάς μας, εξετάστηκαν 11 διαφορετικοί τύποι καρκίνου (καρκίνος του μαστού, καρκίνος του προστάτη, καρκίνος του τραχήλου της μήτρας, καρκίνος του πνεύμονα, καρκίνος του παχέος εντέρου, λευχαιμία, καρκίνος του στόματος, καρκίνος των ωοθηκών, καρκίνος του θυρεοειδούς, καρκίνος του ήπατος, καρκίνος των οστών), καθώς και μια μελέτη πρόβλεψης της αποτελεσματικότητας της χημειοθεραπείς, και καταγράφτηκε για κάθε επιμέρους μελέτη ο κλινικός σκοπός (πχ διάγνωση, πρόβλεψη υποτροπής κτλ), τα δεδομένα που χρησιμοποιήθηκαν (πχ κλινικά, απεικονιστικά, γονιδιακά), οι μέθοδοι ταξινόμησης (πχ τεχνητά νευρωνικά δίκτυα, Μπεϋζιανά δίκτυα) και τα γενικά αποτελέσματα (έξοδος του συστήματος και παράμετροι ακρίβειας, ευαισθησίας, ειδικότητας κτλ). Όλα τα παραπάνω παρουσιάζονται σε έναν συγκεντρωτικό πίνακα στο τέλος της μελέτης ώστε να καταστεί δυνατή η επισκόπησή της και να τεθούν υπό συζήτηση συμπεράσματα, περιορισμοί και μελλοντικές συστάσεις. Αποδείχθηκε ότι η πλειονότητα των συστημάτων υποστήριξης κλινικών αποφάσεων επέδειξε εντυπωσιακά αποτελέσματα πρόβλεψης, γεγονός που ενισχύει την πεποίθησή μας ότι η ενσωμάτωση των συστημάτων αυτών σε κλινικές και νοσοκομειακές εφαρμογές είναι απαραίτητη και θα αποδειχθεί μεγάλης σημασίας στα επόμενα χρόνια.Cancer has proven to be theplague of our time, as it is being placed by the statistics as the second cause of death worldwide. Although early cancer detection and diagnosis are major steps for fighting the disease, cancer prognosis remains equally important. Prognosis relates with the prediction of the likelihood of cancer, as well as the prediction of a patient’s relapse or survival (life expectancy). All the above have been the object in several recently published studies. The researchers have attempted to develop integrated clinical decision support systems by using machine learning methods and classification algorithms. These systems are able to produce an accurate prediction of the patient’s outcome, which may help clinicians in personalized decision-making. The aim of this diploma thesis is the collection and presentation of studies involving such systems as the ones mentioned above for different types of cancer, the assessment of their results and the extraction of several conclusions regarding the structure of clinical decision support systems, the data used for their creation, training and validation, the classification techniques used and the systems’ performance. In order to conduct our study, we examined 11 different cancer types (breast cancer, prostate cancer, cervical cancer, lung cancer, colorectal cancer, leukemia, oral cancer, ovarian cancer, thyroid cancer, liver cancer, skeletal cancer), as well as a study regarding the effectiveness of chemotherapy. For each single study, we listed the study’s clinical endpoint (eg diagnosis, reccurence), the data used (eg clinical, imaging, genomic), the classification methods (eg artificial neural networks, Bayesian networks) and the system’s results (output, accuracy, sensitivity, specificity). All the above are presented in a collective table at the end of the study in order to facilitate the overview of our work and discuss conclusions, limitations and future recommendations. Ithas been proved that the majority of the systems discussed here have shown quite impressive results in terms of prediction, a fact reinforcing our belief that clinical decision support systems will be a valuable integral part of clinical practice in the years to come.Αγγελική Σ. Παξινο

The use of the biomarkers chlorophylls and carotenoids, for the interpretation of the effects in lemna minor after exposure of two herbicides with different mode of action

The impact of herbicides in aquatic vascular plants is often investigated in toxicity laboratory studies. Lemna minor is a fast growing aquatic vascular plant regularly used as a bioindicator in ecotoxicological dose-response studies. Chlorophylls and carotenoids are among the most commonly used biomarkers when monitoring the effects of toxicants. For this study we chose two herbicides, tritosulfuron and metribuzin, with different modes of action. Tritosulfuron is a sulfonylurea herbicide, an amino acid synthesis inhibitor. Metribuzin, on the other hand, is a triazinone herbicide, a photosystem II inhibitor. In the study we investigated changes in content of photosynthetic pigments, in particular chlorophylls a, b and carotenoids, caused by tritosulfuron and metribuzin in Lemna minor. We also evaluated these changes compared to growth rate (based on frond number) endpoint on this species. The toxicity of the two herbicides was assessed by growth inhibition tests in Lemna minor based on standard OECD protocols (7 day test). Growth inhibition, caused by the two herbicides, was measured daily from day 0 until day 7. The four effect concentrations chosen (EC100, EC75, EC50, EC25), were evaluated from pre-tests. The amounts of chlorophyll a and b as well as carotenoids were measured pectrophotometrically on days 1, 3 and 5 after exposure. Obtained results showed that adverse effects on Lemna minor, based on growth inhibition caused by the herbicides, were not clearly connected with a decrease in chlorophyll a, b and carotenoids content. After exposure to various concentrations of tritosulfuron, Lemna minor chlorophyll and carotenoid content showed a decrease which was more intense as the time of exposure increased. For metribuzin, although there was a decrease in pigment content in high concentration treatments on day 3, on day 5 there was no evident effect in pigment concentrations in any treatment. On the other hand, growth rate was reduced with the increase of the concentration of both herbicides on days 3 and 5; growth rate differed statistically between all concentration treatments, except the lowest concentration. We can conclude that for both herbicides growth rate is a more sensitive endpoint to measure the toxicity than pigments. Moreover, tritosulfuron (the amino acid biosynthesis inhibitor) affects pigment concentration more promptly and more intensely than metribuzin (the photosystem II inhibitor) in concentrations causing similar growth inhibition. Further research on the ways that chlorophylls and carotenoid are affected by these two herbicide categories is necessary

Dual production of polyhydroxyalkanoates and antibacterial/antiviral gold nanoparticles

Gold nanoparticles (AuNPs) have been explored for their use in medicine. Here, we report a sustainable, and cost-effective method to produce AuNPs using a bacterial strain such as Pseudomonas mendocina CH50 which is also known to be a polyhydroxyalkanoate (PHA) producer. A cell-free bacterial supernatant, which is typically discarded after PHA extraction, was used to produce spherical AuNPs of 3.5 ± 1.5 nm in size as determined by Transmission Electron Microscopy (TEM) analysis. The AuNPs/PHA composite coating demonstrated antibacterial activity against Staphylococcus aureus 6538P, and antiviral activity, with a 75% reduction in viral infectivity against SARS-CoV-2 pseudotype virus

Sirtuins and proteolytic systems: implications for pathogenesis of synucleinopathies

Insoluble and fibrillar forms of a-synuclein are the major components of Lewy bodies, a hallmark of several sporadic and inherited neurodegenerative diseases known as synucleinopathies. a-Synuclein is a natural unfolded and aggregation-prone protein that can be degraded by the ubiquitin-proteasomal system and the lysosomal degradation pathways. a-Synuclein is a target of the main cellular proteolytic systems, but it is also able to alter their function further, contributing to the progression of neurodegeneration. Aging, a major risk for synucleinopathies, is associated with a decrease activity of the proteolytic systems, further aggravating this toxic looping cycle. Here, the current literature on the basic aspects of the routes for a-synuclein clearance, as well as the consequences of the proteolytic systems collapse, will be discussed. Finally, particular focus will be given to the sirtuins's role on proteostasis regulation, since their modulation emerged as a promising therapeutic strategy to rescue cells from a-synuclein toxicity. The controversial reports on the potential role of sirtuins in the degradation of a-synuclein will be discussed. Connection between sirtuins and proteolytic systems is definitely worth of further studies to increase the knowledge that will allow its proper exploration as new avenue to fight synucleinopathies.Belem Sampaio-Marques is supported by the fellowship SFRH/BPD/90533/2012 funded by the Fundacao para a Ciencia e Tecnologia (FCT, Portugal). The authors apologize for not citing the pioneering work of many colleagues, as this was not intended as an exhaustive review

In-Situ Water Quality Observations under a Large-Scale Floating Solar Farm Using Sensors and Underwater Drones

The rapid implementation of large scale floating solar panels has consequences to water quality and local ecosystems. Environmental impacts depend on the dimensions, design and proportions of the system in relation to the size of the surface water, as well as the characteristics of the water system (currents, tidal effects) and climatic conditions. There is often no time (and budget) for thorough research into these effects on ecology and water quality. A few studies have addressed the potential impacts of floating solar panels, but often rely on models without validation with in situ data. In this work, water quality sensors continuously monitored key water quality parameters at two different locations: (i) underneath a floating solar park; (ii) at a reference location positioned in open water. An underwater drone was used to obtain vertical profiles of water quality and to collect underwater images. The results showed little differences in the measured key water quality parameters below the solar panels. The temperature at the upper layers of water was lower under the solar panels, and there were less detected temperature fluctuations. A biofouling layer on the floating structure was visible in the underwater images a few months after the construction of the park

Antimicrobial Materials with Lime Oil and a Poly (3-hydroxyalkanoate) Produced via Valorisation of Sugar Cane Molasses

A medium chain-length polyhydroxyalkanoate (PHA) was produced by Pseudomonas mendocina CH50 using a cheap carbon substrate, sugarcane molasses. A PHA yield of 14.2% dry cell weight was achieved. Chemical analysis confirmed that the polymer produced was a medium chain-length PHA, a copolymer of 3-hydroxyoctanoate and 3-hydroxydecanoate, P(3HO-co-3HD). Lime oil, an essential oil with known antimicrobial activity, was used as an additive to P(3HO-co-3HD) to confer antibacterial properties to this biodegradable polymer. The incorporation of lime oil induced a slight decrease in crystallinity of P(3HO-co-3HD) films. The antibacterial properties of lime oil were investigated using ISO 20776 against Staphylococcus aureus 6538P and Escherichia coli 8739, showing a higher activity against the Gram-positive bacteria. The higher activity of the oil against S. aureus 6538P defined the higher efficiency of loaded polymer films against this strain. The effect of storage on the antimicrobial properties of the loaded films was investigated. After one-year storage, the content of lime oil in the films decreased, causing a reduction of the antimicrobial activity of the materials produced. However, the films still possessed antibacterial activity against S. aureus 6538P

Dual production of polyhydroxyalkanoates and antibacterial/antiviral gold nanoparticles

Gold nanoparticles (AuNPs) have been explored for their use in medicine. Here, we report a sustainable, and cost-effective method to produce AuNPs using a bacterial strain such as Pseudomonas mendocina CH50 which is also known to be a polyhydroxyalkanoate (PHA) producer. A cell-free bacterial supernatant, which is typically discarded after PHA extraction, was used to produce spherical AuNPs of 3.5 ± 1.5 nm in size as determined by Transmission Electron Microscopy (TEM) analysis. The AuNPs/PHA composite coating demonstrated antibacterial activity against Staphylococcus aureus 6538P, and antiviral activity, with a 75% reduction in viral infectivity against SARS-CoV-2 pseudotype virus

Preclinical study of peripheral nerve regeneration using nerve guidance conduits based on polyhydroxyalkanaotes

Nerve guidance conduits (NGCs) are used as an alternative to the “gold standard” nerve autografting, preventing the need for surgical intervention required to harvest autologous nerves. However, the regeneration outcomes achieved with the current NGCs are only comparable with autografting when the gap is short (less than 10 mm). In the present study, we have developed NGCs made from a blend of Polyhydroxyalkanoates, a family of natural resorbable polymers. Hollow NGCs made from a 75:25 Poly(3‐hydroxyoctanoate)/Poly(3‐hydroxybutyrate) blend (PHA‐NGCs) were manufactured using dip‐moulding. These PHA‐NGCs showed appropriate flexibility for peripheral nerve regeneration. In vitro cell studies performed using RT4‐D6P2T rat Schwann cell line confirmed that the material is capable of sustaining cell proliferation and adhesion. PHA‐NGCs were then implanted in vivo to repair 10 mm gaps of the median nerve of female Wistar rats for 12 weeks. Functional evaluation of the regenerated nerve using the grasping test showed that PHA‐NGCs displayed similar motor recovery as the autograft, starting from week 7. Additionally, nerve cross‐sectional area, density and number of myelinated cells, as well as axon diameter, fibre diameter, myelin thickness and g‐ratio obtained using the PHA‐NGCs were found comparable to an autograft. This preclinical data confirmed that the PHA‐NGCs are indeed highly promising candidates for peripheral nerve regeneration

Antimicrobial materials with lime oil and a poly(3-hydroxyalkanoate) produced via valorisation of sugar cane molasses

A medium chain-length polyhydroxyalkanoate (PHA) was produced by Pseudomonas mendocina CH50 using a cheap carbon substrate, sugarcane molasses. A PHA yield of 14.2% dry cell weight was achieved. Chemical analysis confirmed that the polymer produced was a medium chain-length PHA, a copolymer of 3-hydroxyoctanoate and 3-hydroxydecanoate, P(3HO-co-3HD). Lime oil, an essential oil with known antimicrobial activity, was used as an additive to P(3HO-co-3HD) to confer antibacterial properties to this biodegradable polymer. The incorporation of lime oil induced a slight decrease in crystallinity of P(3HO-co-3HD) films. The antibacterial properties of lime oil were investigated using ISO 20776 against Staphylococcus aureus 6538P and Escherichia coli 8739, showing a higher activity against the Gram-positive bacteria. The higher activity of the oil against S. aureus 6538P defined the higher efficiency of loaded polymer films against this strain. The effect of storage on the antimicrobial properties of the loaded films was investigated. After one-year storage, the content of lime oil in the films decreased, causing a reduction of the antimicrobial activity of the materials produced. However, the films still possessed antibacterial activity against S. aureus 6538P