Ο ρόλος της τεχνικής χαρτών με αυτόματη οργάνωση (self organizing map) στη λήψη θεραπευτικής απόφασης ενδοεπιθηλιακών αλλοιώσεων τραχήλου μήτρας

Σήμερα, υπάρχουν πολυάριθμες τεχνικές που ανιχνεύουν HPV DNA ή mRNA και θεωρούνται είτε ανταγωνιστικές είτε επικουρικές ως προς το τεστ Παπανικολάου για τον έλεγχο των κολποτραχηλικών επιχρισμάτων. Ωστόσο, καμία τεχνική δεν είναι τέλεια, επειδή η αύξηση της ευαισθησίας συνεπάγεται ταυτόχρονη μείωση της ειδικότητας. Για την επίλυση αυτού του προβλήματος έχουν εφαρμοστεί στο παρελθόν διάφορες τεχνικές που χρησιμοποιούν αποτελέσματα από πολλές εξετάσεις ταυτόχρονα, όπως δέντρα ταξινόμησης και παλινδρόμησης (Classification and Regression Trees – CARTs) και εποπτευόμενα τεχνητά νευρωνικά δίκτυα. Σε αυτή την εργασία χρησιμοποιήθηκαν 1258 περιπτώσεις με αποτελέσματα από τεστ Παπανικολάου, HPV DNA, HPV mRNA και p16, προκειμένου να αξιολογηθούν οι επιδόσεις του αυτο-οργανούμενου χάρτη (Self Organizing Map – SOM). Το SOM είναι ένα τεχνητό νευρωνικό δίκτυο που παρουσιάζει σημαντικά πλεονεκτήματα σε σχέση με τις άλλες μεθοδολογίες, καθώς δεν είναι επιβλεπόμενο (δηλαδή δεν χρειάζεται να γνωρίζουμε σε ποια ομάδα ανήκουν τα περιστατικά κατά την εκπαίδευσή του), μπορεί να διαχειριστεί ελλιπή δεδομένα (κάτι πολύ συνηθισμένο σε πραγματικές μελέτες) και παράγει τοπογραφικούς χάρτες (έτσι, με εύκολο τρόπο γίνονται συσχετίσεις των σημαντικών παραμέτρων στη διάγνωση). Τα αποτελέσματα της εφαρμογής της τεχνικής αυτής ήταν ενθαρρυντικά και οδήγησαν σε πολύ υψηλή ευαισθησία και ειδικότητα στη διάκριση των αλλοιώσεων <CIN2 από ≥CIN2, όπως αυτές αξιολογήθηκαν με ιστολογική εξέταση (όπου ήταν εφικτό). Επιπλέον, οι παραγόμενοι χάρτες μπορούν να βοηθήσουν στον εντοπισμό των σημαντικών δοκιμασιών (tests) για τη διάκριση μεταξύ περιστατικών <CIN2 από ≥CIN2.Nowadays, numerous techniques detecting HPV DNA or mRNA, are viewed as competitors or ancillary techniques to test Papanicolaou. However, no technique is perfect, because sensitivity increases at the cost of specificity. Various methods have been applied to resolve this issue, by using many examination results, such as classification and regression trees and supervised artificial neural networks. In this study, 1258 cases with results from test Pap, HPV DNA, HPV mRNA and p16, were used to evaluate the performance of the Self Organizing Map (SOM), an artificial neural network having three advantages: it is unsupervised, it can tolerate missing data and produces topographical maps. The results of the SOM application were encouraging and leaded to very high sensitivity and specificity for the discrimination of <CIN2 from ≥CIN2 lesions, as these were evaluated histologically (wherever that was possible). Additionally, the produced maps can be helpful in order to detect the important tests for such discrimination

Application of the self organizing map in the therapeutic approach of cervical intraepithelial lesions

Nowadays, numerous techniques detecting HPV DNA or mRNA, are viewed as competitors or ancillary techniques to test Papanicolaou. However, no technique is perfect, because sensitivity increases at the cost of specificity. Various methods have been applied to resolve this issue, by using many examination results, such as classification and regression trees and supervised artificial neural networks. In this study, 1258 cases with results from test Pap, HPV DNA, HPV mRNA and p16, were used to evaluate the performance of the Self Organizing Map (SOM), an artificial neural network having three advantages: it is unsupervised, it can tolerate missing data and produces topographical maps. The results of the SOM application were encouraging and leaded to very high sensitivity and specificity for the discrimination of <CIN2 from ≥CIN2 lesions, as these were evaluated histologically (wherever that was possible). Additionally, the produced maps can be helpful in order to detect the important tests for such discrimination.Σήμερα, υπάρχουν πολυάριθμες τεχνικές που ανιχνεύουν HPV DNA ή mRNA και θεωρούνται είτε ανταγωνιστικές είτε επικουρικές ως προς το τεστ Παπανικολάου για τον έλεγχο των κολποτραχηλικών επιχρισμάτων. Ωστόσο, καμία τεχνική δεν είναι τέλεια, επειδή η αύξηση της ευαισθησίας συνεπάγεται ταυτόχρονη μείωση της ειδικότητας. Για την επίλυση αυτού του προβλήματος έχουν εφαρμοστεί στο παρελθόν διάφορες τεχνικές που χρησιμοποιούν αποτελέσματα από πολλές εξετάσεις ταυτόχρονα, όπως δέντρα ταξινόμησης και παλινδρόμησης (Classification and Regression Trees – CARTs) και εποπτευόμενα τεχνητά νευρωνικά δίκτυα. Σε αυτή την εργασία χρησιμοποιήθηκαν 1258 περιπτώσεις με αποτελέσματα από τεστ Παπανικολάου, HPV DNA, HPV mRNA και p16, προκειμένου να αξιολογηθούν οι επιδόσεις του αυτο-οργανούμενου χάρτη (Self Organizing Map – SOM). Το SOM είναι ένα τεχνητό νευρωνικό δίκτυο που παρουσιάζει σημαντικά πλεονεκτήματα σε σχέση με τις άλλες μεθοδολογίες, καθώς δεν είναι επιβλεπόμενο (δηλαδή δεν χρειάζεται να γνωρίζουμε σε ποια ομάδα ανήκουν τα περιστατικά κατά την εκπαίδευσή του), μπορεί να διαχειριστεί ελλιπή δεδομένα (κάτι πολύ συνηθισμένο σε πραγματικές μελέτες) και παράγει τοπογραφικούς χάρτες (έτσι, με εύκολο τρόπο γίνονται συσχετίσεις των σημαντικών παραμέτρων στη διάγνωση). Τα αποτελέσματα της εφαρμογής της τεχνικής αυτής ήταν ενθαρρυντικά και οδήγησαν σε πολύ υψηλή ευαισθησία και ειδικότητα στη διάκριση των αλλοιώσεων <CIN2 από ≥CIN2, όπως αυτές αξιολογήθηκαν με ιστολογική εξέταση (όπου ήταν εφικτό). Επιπλέον, οι παραγόμενοι χάρτες μπορούν να βοηθήσουν στον εντοπισμό των σημαντικών δοκιμασιών (tests) για τη διάκριση μεταξύ περιστατικών <CIN2 από ≥CIN2

Angiopoietin-2 primes infection-induced preterm delivery.

Current knowledge on the participation of angiopoietin-2 (Ang-2) in the inflammatory process and on the importance of bacterial endotoxins (LPS) in the induction of preterm delivery (PTD) led us to investigate the role of Ang-2/LPS interplay in the pathogenesis of PTD. At a first stage, Ang-2 was measured at the end of the first trimester of pregnancy in the serum of 50 women who delivered prematurely; of 88 women well-matched for age and parity who delivered full-term; and of 20 non-pregnant healthy women. Ang-2 was greater in pregnant than in non-pregnant women. The time until delivery was shorter among those with Ang-2 greater than 4 ng/ml (odds ratio for delivery until week 34; p: 0.040). To further investigate the role of Ang-2 for PTD, an experimental model of PTD induced by the intraperitoneal injection of LPS in mice was used. Ang-2 was administered intraperitoneally before LPS on day 14 of pregnancy. When Ang-2 was administered before the LPS diluent, all mice delivered full-term. However, administration of Ang-2 prior LPS accelerated further the time until delivery. Sacrifice experiments showed that the effect of Ang-2 was accompanied by decrease of the penetration of Evans Blue in the embryos and by increase of its penetration in maternal tissues. In parallel, the concentration of tumour necrosis factor-alpha in the maternal circulation, in fetal tissues and in the placentas was significantly decreased. Results indicate that Ang-2 accelerated the phenomena of PTD induced by LPS. This is related with deprivation of fetal perfusion

Angiopoietin-2 Primes Infection-Induced Preterm Delivery

Current knowledge on the participation of angiopoietin-2 (Ang-2) in the inflammatory process and on the importance of bacterial endotoxins (LPS) in the induction of preterm delivery (PTD) led us to investigate the role of Ang-2/LPS interplay in the pathogenesis of PTD. At a first stage, Ang-2 was measured at the end of the first trimester of pregnancy in the serum of 50 women who delivered prematurely; of 88 women well-matched for age and parity who delivered full-term; and of 20 non-pregnant healthy women. Ang-2 was greater in pregnant than in non-pregnant women. The time until delivery was shorter among those with Ang-2 greater than 4 ng/ml (odds ratio for delivery until week 34; p: 0.040). To further investigate the role of Ang-2 for PTD, an experimental model of PTD induced by the intraperitoneal injection of LPS in mice was used. Ang-2 was administered intraperitoneally before LPS on day 14 of pregnancy. When Ang-2 was administered before the LPS diluent, all mice delivered full-term. However, administration of Ang-2 prior LPS accelerated further the time until delivery. Sacrifice experiments showed that the effect of Ang-2 was accompanied by decrease of the penetration of Evans Blue in the embryos and by increase of its penetration in maternal tissues. In parallel, the concentration of tumour necrosis factor-alpha in the maternal circulation, in fetal tissues and in the placentas was significantly decreased. Results indicate that Ang-2 accelerated the phenomena of PTD induced by LPS. This is related with deprivation of fetal perfusion

The effect of Ang-2 on TNFα.

<p>Pregnant female mice were challenged at 14.5 days after plugging with water for injection (WFI, group A, n = 5), with recombinant human angiopoietin-2 (Ang-2 B, n = 5), with lipopolysaccharide of <i>Escherichia coli</i> O55:B5 (LPS, n = 5) and with Ang-2 followed after two hours with LPS (Ang-2+LPS, n = 7). One day after challenge with LPS, mice were sacrificed. Concentrations of TNFα were measured in the sera of mothers (panel A); in the homogenates of fetuses (panel B); and in the homogenates of the placentas (panel C). P values of statistically comparisons between groups: <u>Comparisons LPS vs WFI </u>^ap<0.0001 LPS vs WFI; ^bp: 0.012. <u>Comparisons LPS vs Ang-2 </u>^cp<0.0001; ^dp: 0.006. <u>Comparisons LPS vs LPS+Ang-2 </u>^ep<0.0001; ^fp: 0.006.</p

Concentrations of Ang-2 during pregnancy.

<p>A) Serum levels of Ang-2 were measured at week 12 in serum of 50 women who delivered prematurely (PTD); of 88 women who delivered full-term; and of 20 non-pregnant healthy women. P values represent comparisons to non-pregnant healthy women. B) Time until delivery in relation with the level of circulating Ang-2 at week 12. P is the value of comparisons between women with serum Ang-2 below and above 4 ng/ml.</p

Tissue penetration of Evans blue.

<p>Female pregnant female mice were challenged at 14.5 days after plugging with water for injection (WFI, group A, n = 5), with recombinant human angiopoietin-2 (Ang-2 B, n = 5), with lipopolysaccharide of <i>Escherichia coli</i> O55:B5 (LPS, n = 5) and with Ang-2 followed after two hours with LPS (Ang-2+LPS, n = 7). One day after challenge with LPS, mice were sacrificed. Evans blue was measured in the fetuses (panel A), in the placentas (panel B), in the kidneys of mothers (panel C) and in the lungs of mothers (panel D). P values indicate statistical significances between the LPS and the LPS+Ang-2 groups.</p

Ang-2 accelerates preterm delivery (PTD).

<p>Female pregnant female mice were challenged at 14.5 days after plugging with water for injection (WFI, group A, n = 6), with recombinant human angiopoieting-2 (Ang-2 B, n = 6), with lipopolysaccharide of <i>Escherichia coli</i> O55:B5 (LPS, n = 6) and with Ang-2 followed after two hours with LPS (Ang-2+LPS, n = 6). The time until delivery of alive offspring was recorded every two hours after challenge with LPS. Statistical comparisons between groups after correction for multiple testing by Bonferroni were: log-rank_{WFI vs LPS:} 13.679, p: 0.000217; log-rank_{WFI vs LPS+Ang-2}: 15.251, p: 0.000094; log-rank_{LPS vs LPS+Ang-2}: 6.290, p: 0.012.</p

Study flow-chart.

<p>PTD: preterm delivery.</p