1,720,976 research outputs found
Assessing the potential role of Rictor expression as predictive factor of response to PI3K/mTOR pathway inhibitors in preclinical models of squamous cell lung cancer
Full text linkSquamous cell lung cancer (SQLC) is the second most prevalent histologic type of lung cancer and accounting for approximately 30% of newly diagnosed non-small cell lung cancer (NSCLC) cases. Systemic treatments for SQLC patients include cytotoxic chemotherapy and immune-oncology approaches. In contrast with lung adenocarcinoma, which is the other main subtype of NSCLC, no patient-tailored treatments are available so far for SQLC. Accumulating evidence suggests that the PI3K/mTOR axis is one of the most frequently altered pathways in SQLC. However, despite a plethora of clinical trials with numerous PI3K/mTOR targeted inhibitors, no significant increase in patients’ survival has been observed as compared to standard treatment options. A possible explanation for the outcome of those clinical trials might be the lack of reliable predictive biomarkers for better patients’ stratification. We and others have reported Rictor copy number gain (CNG) in a set of SQLC patients by performing targeted DNA sequencing on archival tissues. Another group has suggested the existence of Rictor focal amplification in subsets of lung cancers, including SQLC, and further suggested Rictor as a potential predictive biomarker of response to targeted therapy. However, no conclusive data were presented to show that Rictor amplification is driving activation of the PI3K/mTOR pathway in SQLC cells or representing a valid biomarker predictive of response to targeted inhibition of the pathway. Here, we used three different SQLC cell lines and 60 tissue specimens to show that CNG of Rictor is a recurrent event in SQLC, yet this is due to the polysomy of the short arm of chromosome 5 rather than to focal amplification. All three cell lines tested showed different Rictor CNG and different levels of its transcript and protein. In particular, the SQLC cell line harboring the higher CNG (H-1869) accordingly displayed higher level of Rictor protein. Therefore, we sought to test the possibility that the dosage of Rictor might affect the activation of PI3K/mTOR pathway and sensitivity towards its targeting agents. Unexpectedly, we found that Rictor levels did not parallel the biochemical activation of the pathway nor the sensitivity to dual mTORC1/C2 or PI3K/mTOR inhibitions. These observations were confirmed by genetic perturbation analysis, as reduction of Rictor levels through RNA interference did not lead neither to reduced cell viability nor to significant changes in drug sensitivity in the two cell lines tested. Overall, our findings suggest that Rictor does not represent a predictive biomarker of response towards PI3K/mTOR directed therapy
Η μελέτη της έκφρασης του γονιδίου Rictor ως πιθανός βιοδείκτης της ανταπόκρισης σε αναστολείς του PI3K/mTOR σηματοδοτικού μονοπατιού σε προκλινικά μοντέλα πλακώδους καρκίνου του πνεύμονα
No full textSquamous cell lung cancer (SQLC) is the second most prevalent histologic type of lung cancer and accounting for approximately 30% of newly diagnosed non-small cell lung cancer (NSCLC) cases. Systemic treatments for SQLC patients include cytotoxic chemotherapy and immune-oncology approaches. In contrast with lung adenocarcinoma, which is the other main subtype of NSCLC, no patient-tailored treatments are available so far for SQLC. Accumulating evidence suggests that the PI3K/mTOR axis is one of the most frequently altered pathways in SQLC. However, despite a plethora of clinical trials with numerous PI3K/mTOR targeted inhibitors, no significant increase in patients’ survival has been observed as compared to standard treatment options. A possible explanation for the outcome of those clinical trials might be the lack of reliable predictive biomarkers for better patients’ stratification. We and others have reported Rictor copy number gain (CNG) in a set of SQLC patients by performing targeted DNA sequencing on archival tissues. Another group has suggested the existence of Rictor focal amplification in subsets of lung cancers, including SQLC, and further suggested Rictor as a potential predictive biomarker of response to targeted therapy. However, no conclusive data were presented to show that Rictor amplification is driving activation of the PI3K/mTOR pathway in SQLC cells or representing a valid biomarker predictive of response to targeted inhibition of the pathway. Here, we used three different SQLC cell lines and 60 tissue specimens to show that CNG of Rictor is a recurrent event in SQLC, yet this is due to the polysomy of the short arm of chromosome 5 rather than to focal amplification. All three cell lines tested showed different Rictor CNG and different levels of its transcript and protein. In particular, the SQLC cell line harboring the higher CNG (H-1869) accordingly displayed higher level of Rictor protein. Therefore, we sought to test the possibility that the dosage of Rictor might affect the activation of PI3K/mTOR pathway and sensitivity towards its targeting agents. Unexpectedly, we found that Rictor levels did not parallel the biochemical activation of the pathway nor the sensitivity to dual mTORC1/C2 or PI3K/mTOR inhibitions. These observations were confirmed by genetic perturbation analysis, as reduction of Rictor levels through RNA interference did not lead neither to reduced cell viability nor to significant changes in drug sensitivity in the two cell lines tested. Overall, our findings suggest that Rictor does not represent a predictive biomarker of response towards PI3K/mTOR directed therapy.Το πλακώδες καρκίνωμα του πνεύμονα (ΠΚΠ) είναι ο δεύτερος πιο διαδεδομένος ιστολογικός τύπος καρκίνου του πνεύμονα και αντιπροσωπεύει περίπου το 30% των νέων περιπτώσεων μη μικροκυτταρικού καρκίνου του πνεύμονα (ΜΜΚΠ). Οι συστηματικές θεραπείες για ασθενείς με ΠΚΠ περιλαμβάνουν προσεγγίσεις κυτταροτοξικής χημειοθεραπείας και ανοσοογκολογίας. Σε αντίθεση με το αδενοκαρκίνωμα του πνεύμονα, που είναι ο άλλος κύριος υποτύπος του ΜΜΚΠ, δεν υπάρχουν μέχρι στιγμής διαθέσιμες θεραπείες προσαρμοσμένες στον ασθενή για το ΠΚΠ. Τα συσσωρευμένα στοιχεία υποδηλώνουν ότι ο άξονας PI3K/mTOR είναι ένα από τα μονοπάτια που αλλάζουν πιο συχνά στο ΠΚΠ. Ωστόσο, παρά την πληθώρα κλινικών δοκιμών με πολλούς στοχευμένους αναστολείς PI3K/mTOR, δεν έχει παρατηρηθεί σημαντική αύξηση στην επιβίωση των ασθενών σε σύγκριση με τις τυπικές θεραπευτικές επιλογές. Μια πιθανή εξήγηση για το αποτέλεσμα αυτών των κλινικών δοκιμών μπορεί να είναι η έλλειψη αξιόπιστων προγνωστικών βιοδεικτών για καλύτερη κατηγοριοποίηση των ασθενών. Εμείς όπως και άλλοι έχουμε αναφέρει αύξηση αριθμού αντιγράφων του γονιδίου Rictor (CNG) σε ένα σύνολο ασθενών με ΠΚΠ πραγματοποιώντας στοχευμένη αλληλουχία DNA σε αρχειακούς ιστούς. Μια άλλη ομάδα πρότεινε την ύπαρξη εστιακής ενίσχυσης του γονιδίου Rictor σε υποομάδες καρκίνων του πνεύμονα, συμπεριλαμβανομένου του ΠΚΠ, και πρότεινε περαιτέρω το Rictor ως πιθανό προγνωστικό βιοδείκτη ανταπόκρισης σε στοχευμένη θεραπεία. Ωστόσο, δεν παρουσιάστηκαν οριστικά δεδομένα που να δείχνουν ότι η ενίσχυση του γονιδίου Rictor οδηγεί σε ενεργοποίηση του σηματοδοτικού μονοπατιού PI3K/mTOR σε κύτταρα ΠΚΠ ή αντιπροσωπεύει έναν έγκυρο βιοδείκτη που προγνωστοποιεί την απόκριση στη στοχευμένη αναστολή της οδού. Εδώ, χρησιμοποιήσαμε τρεις διαφορετικές κυτταρικές σειρές ΠΚΠ και 60 δείγματα ιστού για να δείξουμε ότι το CNG του Rictor είναι ένα επαναλαμβανόμενο συμβάν στο ΠΚΠ, ωστόσο αυτό οφείλεται στην πολυσωμία του μικρού βραχίονα του χρωμοσώματος 5 και όχι στην εστιακή ενίσχυση. Και οι τρεις κυτταρικές σειρές που εξετάστηκαν έδειξαν διαφορετικό Rictor CNG και διαφορετικά επίπεδα μεταγραφής και πρωτεΐνης του. Συγκεκριμένα, η κυτταρική σειρά ΠΚΠ που περιέχει το υψηλότερο CNG (H-1869) επέδειξε αντίστοιχα υψηλότερο επίπεδο πρωτεΐνης Rictor. Ως εκ τούτου, επιδιώξαμε να ελέγξουμε την πιθανότητα ότι η δόση του γονιδίου Rictor μπορεί να επηρεάσει την ενεργοποίηση της οδού PI3K/mTOR και την ευαισθησία προς τους παράγοντες στόχευσής του. Απροσδόκητα, διαπιστώσαμε ότι τα επίπεδα του γονιδίου Rictor δεν ήταν παράλληλα με τη βιοχημική ενεργοποίηση της οδού ούτε με την ευαισθησία σε διπλούς αναστολείς mTORC1/C2 ή PI3K/mTOR. Αυτές οι παρατηρήσεις επιβεβαιώθηκαν με ανάλυση γενετικής διαταραχής, καθώς η μείωση των επιπέδων Rictor μέσω παρεμβολής RNA δεν οδήγησε ούτε σε μειωμένη κυτταρική βιωσιμότητα ούτε σε σημαντικές αλλαγές στην ευαισθησία του φαρμάκου στις δύο κυτταρικές σειρές που δοκιμάστηκαν. Συνολικά, τα ευρήματά μας υποδηλώνουν ότι το Rictor δεν αντιπροσωπεύει έναν προγνωστικό βιοδείκτη ανταπόκρισης στην κατευθυνόμενη θεραπεία με PI3K/mTOR
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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