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1
Starodubcev, Tatjana. « Predstava starozavetnog Veseleila u oltaru Ravanice ». Zbornik radova Vizantoloskog instituta, no 39 (2001) : 249–63. http://dx.doi.org/10.2298/zrvi0239249s.
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(francuski) Dans l'?glise de Ravanica les faces frontales des deux pilastres flanquant l'abside centrale et marquant la limite de la proth?se, respectivement du diaconicon, accueillent deux personnages v?t?rotestamentaires, chacun s?par? de la sc?ne de la Communion des ap?tres par la figure d'un archipr?tre. Sur le pilastre nord se tient Melchis?dek, et sur celui situ? au sud, un homme aux cheveux courts et ? la barbe arrondie, v?tu d'un chiton et d'un hymation, qui tient en mains un objet de forme ronde orn? d'une repr?sentation en buste de la Vierge ? l'Enfant, et ? c?t? duquel subsistent les traces d'une inscription (fig. 1)Selon l'Ancien Testament et l'Ep?tre aux H?breux, le juste Melchis?dek ?tait le sacrificateur du Dieu Tr?s-Haut et sup?rieur aux sacrificateurs l?vitiques. C'est lui qui offre en sacrifice le pain et le vin, et plus tard le Christ lui-m?me est devenu "sacrificateur pour toujours, selon l'ordre de Melchis?dek". Sur le pilastre sud, les restes d'inscription o? l'on reconna?t le d?but d'un nom montre que le personnage ici repr?sent? pourrait ?tre le juste Betsaleel qui est mentionn? ? plusieurs reprises dans l'Exode en tant que fils d'Uri de la tribu de Juda etque Dieu a choisi en lui accordant la sagesse, l'intelligence et le savoir pour toutes sortes d'ouvrages afin qu'il p?t construire l'Arche du t?moignage.Ce personnage biblique n'est pas c?l?br? par le Calendrier de l'Eglise constan-tinopolitaine et, pour autant qu'on le sache, n'est repr?sent? que dans quatre manuscrits: la Sacra parallela (Paris gr. 923), du IX?me si?cle; le psaultier n? 61 du monast?re athonite du Pantocrator, du IX?me si?cle; l'ochtateuque de la Biblioth?que du Vatican gr. 747, du Xl?me si?cle; et l'ochtateuque d'Istanbul Seraglio cod. 8, du Xll?me si?cle, o? il appara?t figur? de diff?rentes fa?ons. Dans le manuscrit la Sacra parallela il a les traits d'un vieillard, dans le psaultier d'un homme d'?ge moyen ? la barbe arrondie et aux cheveux longs, alors que dans les ochtateuques il porte les cheveux courts, lisses et drus, avec la raie sur le c?t?. De toute ?vidence, les peintres avaient toute libert? lors de la repr?sentation de ce juste, et il importe donc, en premier lieu, de rechercher les raisons de la pr?sence ici de ce saint si rarement figur?. En tant que constructeur du Tabernacle, sa place dans le sanctuaire d'une ?glise est tout ? fait justifi?e, puisque on rencontre aussi des repr?sentations du Tabernacle dans le narthex, et plus souvent encore dans l'espace du sanctuaire. Dans ce second espace la pr?sence du Tabernacle est notamment justifi?e par les diff?rents niveaux de sa symbolique puisque les plus anciennes interpr?tations et commentaires le per?oivent comme une pr?figuration du Tabernacle c?leste, comme le sanctuaire dans lequel le Christ se sacrifie et proc?de au sacrifice, puis il est ?galement devenu le symbole de la Vierge, alors que plus tard sont apparues des interpr?tations qui l'ont rattach? au contexte liturgique. Betsaleel n'a pas fait l'objet d'une attention particuli?re de la part de la science et l'on ne peut qu'indiquer la direction dans laquelle est all?e la pens?e th?ologique ? son sujet. A en juger par une observation sommaire des textes, et nonobstant, son ?vocation par les textes philosophiques pr?coces, il n'est que tr?s rarement mentionn? (Philon d'Alexandrie, premi?re moiti? du 1er si?cle, Orig?ne, vers 185-254, Cyrille de J?rusalem, vers 315-386, Basile le Grand, vers 330-379, Th?odoret de Cyr, vers 393 vers 458, Cosmas Indicopleust?s, milieu du Vl?me si?cle). Tous ces ?crits le montrent comme un mod?le d'artisan auquel Dieu, conform?ment au texte biblique de l'Exode, a donn? la sagesse, l'intelligence, le savoir pour toutes sortes d'ouvrages et qu'il a d?sign? pour ?tre le constructeur du Tabernacle, en soulignant toujours le fait que Dieu est celui dont viennent toutes ces vertus. Dans toutes ces interpr?tations il reste dans l'ombre de Dieu en tant que Cr?ateur supr?me. De m?me, Betsaleel est rarement mentionn? dans les autres sources ?crites et, lorsque cela est le cas, il y est d'ordinaire pr?sent? comme un constructeur, comme un mod?le pour les b?tisseurs d'?glises qui sont compar?s ? lui (Eus?be de C?sar?e, vers 260-339; l'hymne syriaque "Sogitha" consacr? ? la sanctification de l'?glise Sainte-Sophie ? Edesse apr?s sa reconstruction en 553/554; la Vie de saint Sim?on le Stylite le Jeune (?592) du diacre St?phane; la pri?re prononc?e par le patriarche lors de la cons?cration de l'?glise et de la sainte table, d'apr?s le plus ancien euchologion enti?rement conserv? de l'?glise Sainte-Sophie de Constantinople, Barb. gr. 336, milieu du VHI?me si?cle; la comm?moraison de la tr?s pieuse imp?ratrice Ir?ne, femmede Jean Comn?ne (1118-1143), dans le Synaxaire de l'Eglise constantinopolitaine; l'inscription m?trique de fondation de l'?glise saint-Nicolas pr?s du village de Place dans la p?ninsule de Mani au sud du P?lopon?se, de 1337/38). A Ravanica Betsaleel ne porte pas le mod?le du tabernacle, mais un objet de forme ronde orn? d'un buste de la Vierge ? l'Enfant (semblable ? l'image de la sainte table dans le sanctuaire de la Chapelle de Mo?se au Sina?). Betsaleel ?tant lou? comme le constructeur du Tabernacle et les cantiques eccl?siastiques c?l?brant la M?re de Dieu comme ?tant elle-m?me le Tabernacle; son image, tenant le Christ dans ses bras, sur l'objet que porte Betsaleel s'en trouve tout ? fait justifi?e, comme sur de nombreuses repr?sentations de la Tente d'assignation o? elle appara?t en m?daillon sur le voile recouvrant l'autel et sur les objets pos?s sur celui-ci. On doit se demander pourquoi le choix du d?corateur s'est ici port? pr?cis?ment sur Melchis?dek et Betsaleel. Le premier, en tant que sacrificateur v?t?rotesta-mentaire sur le mod?le duquel le Christ est lui-m?me devenu sacrificateur, avait d?j? ?t? figur? dans les sanctuaires des premi?res ?glises chr?tiennes, alors que l'image de Betsaleel, pour autant que nous sachions, constitue un exemple unique. Melchis?dek se tient ? proximit? de la partie septentrionale, et c?leste, de la composition de la Communion des ap?tres, o? la communion par le pain est donn?e par un ange-pr?tre, alors que Betsaleel, au sud, c?toie la partie terrestre, montrant un pr?tre, debout dans le sanctuaire, qui tend un calice. Le constructeur du Tabernacle se trouve ainsi ? c?t? d'un l'?v?nement qui se d?roule dans l'?glise, alors que le pr?tre v?t?rotestamentaire se tient ? c?t? de l'?glise c?leste et spirituelle. L'existence d'un fort lien avec la liturgie est ?galement confirm?e par les deux ?v?ques qui se tiennent aux c?t?s de ces justes et les d?signent de la main droite (fig. 2). Leurs inscriptions ont ?t? d?truites, mais leurs tenues, diff?rentes des tenues habituelles d'?v?ques, autorisent ? reconna?tre en eux les premiers ?v?ques de J?rusalem auxquels la haute dignit? d'archi-pr?tre a ?t? transmise, d'apr?s la tradition, par le Christ en personne. En observant les donn?es provenant de la Bible, les ?crits des P?res de l'Eglise et certaines mentions relatives aux constructeurs d'?glises, il est donc possible de supposer que ce juste repr?sent? ? Ravanica est Betsaleel, le constructeur v?t?rotestamentaire du Tabernacle. L'?troit lien le rattachant ? la liturgie justifie pleinement sa pr?sence dans l'espace du sanctuaire. L'hypoth?se ici avanc?e est ?galement confirm?e par l'existence de rapports avec la figure du juste Melchis?dek et celles des premiers ?v?ques de l'Eglise de Sion, ainsi qu'avec la repr?sentation, unique par son iconographique, de la Communion dans l'abside. .
2
Leclair, Yves. « Jean-Pierre Rosa, La ville, Nouvelle Cité, « Ce que dit la Bible sur… », n° 34, 2018, 128 pages, 13 €. » Études Janvier, no 1 (20 décembre 2018) : XL. http://dx.doi.org/10.3917/etu.4256.0117an.
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Michielin, Maico. « Bridging the gulf between biblical scholars and theologians : Can Barth and Wright provide an answer ? » Scottish Journal of Theology 61, no 4 (novembre 2008) : 420–34. http://dx.doi.org/10.1017/s0036930608004183.
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AbstractThere was a time when the interpretation of the Bible was a seamless integrated theological activity. Today, the separation of biblical studies from theologically interested exegesis amongst theologians encourages a sceptical arms-length relationship between Old and New Testament scholars and theologians. Theologians criticise biblical studies' so-called objective and disinterested approach to interpreting the Bible for requiring scholars of both testaments to suspend their theological convictions. Biblical scholars condemn theologians for misusing biblical texts in support of their own preconceived theological agendas. The article suggests a way to bring these divergent exegetical approaches into conversation in a charitable, yet critical fashion, by comparing Karl Barth and N. T. Wright's exegesis of Romans 3:21–4:25. It concludes that the biblical scholar's and theologian's respective sensitivity to the historical and theological sense of the biblical text can, when brought together, benefit each other's reading of the Bible.
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Boisclair, Regina. « Interpreting Scripture : Essays on the Bible and Hermeneutics by N. T. Wright, and : Interpreting Jesus : Essay on the Gospels by N. T. Wright, and : Interpreting Paul : Essays on the Author and His Letters by N. T. Wright ». Catholic Biblical Quarterly 84, no 2 (avril 2022) : 352–54. http://dx.doi.org/10.1353/cbq.2022.0083.
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Trojanowska, Mariola. « David G. Firth – Brittany N. Melton (eds.), Reading Esther Intertextually, Library of Hebrew Bible/Old Testament Studies 725, Bloomsbury T&T Clark, London 2022, pp. 240. » Collectanea Theologica 93, no 3 (28 août 2023) : 227–31. http://dx.doi.org/10.21697/ct.2023.93.3.10.
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Grozdanov, Cvetan. « O Sv. Konstantinu Kavasili i njegovim portretima u svetlu novih saznanja ». Zbornik radova Vizantoloskog instituta, no 44 (2007) : 313–24. http://dx.doi.org/10.2298/zrvi0744313g.
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(francuski) L?auteur de cet article revient a l??tude du personnage de l?archev?que Constantin Cabasilas et de ses portraits dans le cadre de ses nouvelles d?couvertes (ZLU, 2, Novi Sad 1966) et dans la lumi?re des ?tudes d?autres auteurs. Dans cet article, on souligne particuli?rement le fait que la figure de saint Nicolas de Myre appartient au groupe d?hi?rarques peint sur le mur nord de l??glise Sainte-Vierge-Perivleptos a Ohrid, en commun avec saint Clement et saint Constantin Cabasilas, ce qui m?ne a la conclusion que ce groupe n?est pas le seul groupe th?matique de saints d?Ohrid. L?auteur s?attarde a l?inscription portant le nom de Cabasilas grav?e sur le pilier de la galerie de Gregoire de 1313/14 et ?met l?hypoth?se que la m?moire de Cabasilas ?tait ?galement pr?sente dans l?annexe sud de l??glise Sainte-Sophie, r?cemment fouill?e. L?annexe de Sainte-Sophie occupe une surface ?norme, elle a ?t? peinte dans la deuxi?me moitie du 13e si?cle, ce que l?on peut d?duire gr?ce au grand nombre de fragments trouves ou conserves in situ. L?auteur exprime sa r?serve quant a l?opinion exprim?e ant?rieurement que saint Constantin Cabasilas a ?t? peint dans le narthex de l??glise Sainte-Vierge- -Perivleptos a la t?te du cort?ge d?hi?rarques dans la Stychire de Noel de Jean Damasc?ne, et il consid?re qu?il s?agit de la figure de saint Jean Chrysostome avec lequel Cabasilas a des ressemblances physionomiques. Plus exactement, dans ce premier cort?g? a cote du tr?n? avec la Vierge, l?auteur reconnait saint Basile le Grand, saint Jean Chrysostome saint Gr?goire le Th?ologien et partiellement la figure de saint Athanase le Grand. Derri?re eux vient le cort?ge des saints empereurs chretiens avec saint Constantin et sainte Helene en t?te. On suppose que derri?re eux sont peints les empereurs de la dynastie des Pal?ologues. Puisque la figure du Protaton montre Cabasilas en tant que vieil homme (a la diff?rence de ses portraits a Ohrid et a Staro Nagoricino), on ?met l?hypoth?se que saint Cabasilas, saint Erasme, saint Theophilacte et saint Cl?ment du Protaton (chapelle de Saint-Jean le Pr?curseur, 1526) ont ?t? peints selon l?original d?Ohrid qui n?est plus conserve vu la destruction de Sainte-Sophie et de Saint-Panteleimon de Cl?ment sous la domination turque. La cr?ation de l?ensemble au Protaton qui ?tait ?tudie par G. Subotic en tant que donation de l?archipr?tr? Gabriel, est particuli?rement mis en relief aussi en rapport avec la peinture des saints d?Ohrid mentionnes dans la chapelle de Saint-Jean le Pr?curseur. L?auteur de cet article attire une attention particuli?re sur la d?couverte de la vie et de l?office de Constantin Cabasilas ou on fait mention du jour de sa mort (le 18 octobre), ce qui signifie qu?il a ?t? canonise. Ensuite, on indique les copies des canons des Quinze martyrs de Strumica, publi?es plus tard (en grec et en slave), de la Biblioth?que nationale de Belgrade et de Sofia, ainsi que celles de l??parchie de Strumica. On souligne l?importance des canons de Cabasilas consacres a saint Cl?ment et a saint Naum dans lesquels, selon les notes de K. Nichoritis l?auteur parle des souffrances et des peines injustes subies dans la prison de Nic?e, ?galement mentionn?es dans la vie r?dig?e par son disciple inconnu d?Ohrid. Au sujet du culte de saint C. Cabasilas, on signale que sa canonisation est due a sa popularit? dans le dioc?se d?Ohrid ou il a travaille pendant plus de 40 ans en tant qu?hi?rarque de Strumica et de Durres et en tant qu?archev?que d?Ohrid. En m?me temps, on souligne sa collaboration avec Michel VIII Pal?ologue, c?est-a-dire avec son fr?re Jean lors de la prise d?Ohrid par les Nic?ens, ce qui repr?sentait en quelque sorte sa r?habilitation durant le long r?gne d?Andronique II Pal?ologue. L?auteur signale que les donn?es relatives a la date de la mort de C. Cabasilas, ainsi que celles concernant son h?ritier sur le tr?ne d?Ohrid ne sont pas connues.
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Kim, Uriah Y. « Dictionary for Theological Interpretation of the Bible – Edited by Kevin J. Vanhoozer, Craig G. Bartholomew, Daniel J. Treier and N. T. Wright ». Reviews in Religion and Theology 13, no 4 (septembre 2006) : 483–84. http://dx.doi.org/10.1111/j.1467-9418.2006.00309_9.x.
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Backus, Irena. « Renaissance Attitudes to New Testament Apocryphal Writings : Jacques Lèfevre d'Étaples and His Epigones ». Renaissance Quarterly 51, no 4 (1998) : 1169–98. http://dx.doi.org/10.2307/2901964.
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AbstractThe standard medieval view of New Testament Apocrypha was that they were Christian writings (related to matters treated in the canonical books of the Bible), which had to be treated with caution and often dismissed as heretical. A list of the Apocrypha figured in the [Pseudo-]Gelasian Decree. In the Renaissance, for authors such as Lèfevre d'Etaples, Nicholas Gerbel and many others, the term assumed a multiplicity of meanings, both positive and negative. This article shows that although no attempts were made in the early 16th century to bring N. T. Apocrypha together into a corpus, the editors' ambivalent and complex attitude to texts such as the Laodiceans or Paul's Correspondence with Seneca led to their definitive marginalisation and encouraged their subsequent publication (by Fabricius and others) as corpora of dubious writings.
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Milenkovic, Ivan. « La volonté générale comme une fiction théorico-politique : Rousseau et le concept de la souveraineté ». Filozofija i drustvo 23, no 3 (2012) : 135–47. http://dx.doi.org/10.2298/fid1203135m.
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Dans ce texte l?auteur examine les rapports entre les concepts du contrat social, de la souverainet? et de la volont? g?n?rale chez Jean-Jacques Rousseau. D?un c?t? ils sont dans les intrins?ques relations mutuelles. De l?autre ce n?est que le concept de la souverainet? qui evite les implications metaphisiques et le statut de la fiction th?orico-politique dans l?oeuvre de Rousseau. La volont? g?n?rale, au contraire, reste en ?tat de la fiction th?orico-politique ? cause de la pressuposition rousseau?nne sur l?unit? du corps politique qui, donc, ne doit ?tre dommager par l?existences des fractions et des parties en dedans. ? savoir, Rousseau ne pouvais pas renonc? de la communaut? comme un ensemble organique, il ne pouvait pas donner l?avantage d?une partie ? l?egard du tout, car il n?avait pas, ? l?epoque, les instrum?ments conceptuels adequats.
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Calvet, Antoine. « Hilaire de Poitiers, Commentaires sur les Psaumes, t. V, (Psaumes 119‑126), texte critique du CCL 61B (Jean Doignon), traduction, n ». Revue de l'histoire des religions, no 241 (1 mars 2024) : 139–41. http://dx.doi.org/10.4000/rhr.12970.
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Cho, Jaecheon. « Making Sense of Virus with the Bible : A Comparative Analysis of Biblical Reflections on Coronavirus by Walter Brueggemann, N. T. Wright, and John Piper ». Korean New Testament Studies 28, no 4 (31 décembre 2021) : 785–817. http://dx.doi.org/10.31982/knts.2021.12.28.4.785.
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Poumeaud, François, Mathilde Morisseau, Luc Cabel, Anthony Gonçalves, Charlène Rivier, Olivier Trédan, Elsa Volant et al. « Abstract PS08-02 : Efficacy of Sacituzumab-Govitecan (SG) post Trastuzumab-deruxtecan (T-DXd) and vice versa for HER2low advanced or metastatic breast cancer (MBC) : a French multicentre retrospective study ». Cancer Research 84, no 9_Supplement (2 mai 2024) : PS08–02—PS08–02. http://dx.doi.org/10.1158/1538-7445.sabcs23-ps08-02.
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Abstract Background: Based on ASCENT, TROPICS-02 and DESTINY-Breast04 trials, SG and T-DXd recently became approved for HER2low MBC. Since the payloads of both SG and T-DXd belong to the same cytotoxic class (topoisomerase-1 inhibitor), cross-resistance is a potential concern. However, no data is available on the efficacy of one antibody drug conjugate (ADC) after another and the best therapeutic sequence has not been evaluated yet. Methods: We conducted a retrospective study in 19 French comprehensive cancer centres. All patients (pts) with HR+ or HR- and HER2low MBC treated with SG followed, immediately or not, by T-DXd (or vice versa) were included. HR expression was defined on the last available tumor sample. The study primary objective was to report the second ADC (ADC2) progression-free survival (PFS) in the whole population. Secondary objectives included first ADC (ADC1) progression-free interval (PFI) and overall survival (OS) in the whole population and subgroup analyses by HR status. Results: The individual data of 126 eligible women were obtained from 19 participating centres. Median age was 54.5 years (range: 30-80y). N=110 (87.3%) pts had invasive carcinoma of not special type, N=12 (9.5%) invasive lobular carcinoma and 4 (3.2%) other histological subtype. N=87 (69%) and 39 (31%) had HR+/HER2low and HR-/HER2low MBC, respectively. N=16 patients were germline mutation carriers (BRCA1 N=7; BRCA2 N=6; other genes on HBOC panel N=3). ADC1 was given as a median of third (range: 1-10) line of chemotherapy and ADC2 as fifth (range: 2-12) line. A large majority (N=94, 74.6%) of pts received SG as ADC1 (N=82 with HR- and N=12 with HR+ MBC) while N=32 (25.4%) received T-DXd as ADC1 (N=27 with HR+ and n=5 with HR- MBC). 53.2% (N=67) received ADC1 immediately followed by ADC2 while 46.8% (N=59) received ADC2 after 1 (N=40) or 2 (N=12) or ≥ 3 (N=6) other lines of chemotherapy. N=19 (15.07%) and N=26 (20.63%) had a meningeal and/or cerebral metastasis at the time of the initiation of ADC1 and ADC2 respectively. After a median follow-up of 3 months, ADC2 was discontinued in 63 pts of which 51 (82.3%) for progression disease and 4 (6.5%) for toxicity due to T-DXd. Importantly, 50% of pts (N=63) were still under ADC2 at the time of this first analysis. The observed median PFS for ADC2 and median PFI for ADC1 are presented in the Table below: Median OS was not reached independently of the sub-populations of pts. Population and sequential regimen Median (mo) PFI ADC1 Median (mo) PFS ADC2 Whole population (N=126) SG → T-DXd (N=94) T-DXd→SG (N=32) 4.5 (95%CI [3.4-5.1]) 2.7 (95%CI [2.1-3.3] HR-/HER2low (N=82) having received SG as ADC1 then T-DXd as ADC2 4.8 (95%CI [3.8-5.1]) 3.3 (95%CI [2.5-3.7]) HR+/HER2low (n=27) having received T-DXd as ADC1 then SG as ADC2 2.7 (95%CI [2.0-3.2]) 2.0 (95%CI [1.6-NR]) Conclusion: To the best of our knowledge, this is the largest cohort evaluating the efficacy of subsequent ADCs administration in HER2low MBC. In these heavily pre-treated pts, subsequent use of ADCs seem to be associated with shortened PFS in both HR+/HR- subgroups, independently of their administration order. Data will be updated and completed for the meeting. Moreover, the number of eligible pts will be increased. Table 1: median TPP and PFS2 in whole population and HR subgroups Citation Format: François Poumeaud, Mathilde Morisseau, Luc Cabel, Anthony Gonçalves, Charlène Rivier, Olivier Trédan, Elsa Volant, Jean Sebastien FRENEL, Sylvain Ladoire, William Jacot, Mathieu Jamelot, Hervé Fokatichoue, Luis Teixeira, Francois-Clement Bidard, Delphine Loirat, Christelle Levy, Bastien Cabarrou, Antoine Deleuze, Elise Deluche, Thomas Grellety, Frédéric Fiteni, Hervé Bischoff, Roman Vion, Stéphanie Becourt, Thibaut Reverdy, Alexandre de Nonneville, Florence Dalenc. Efficacy of Sacituzumab-Govitecan (SG) post Trastuzumab-deruxtecan (T-DXd) and vice versa for HER2low advanced or metastatic breast cancer (MBC): a French multicentre retrospective study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-02.
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Bauks, Michaela. « La « chute » de Caïn en Genèse 4,1-16. Le mal inévitable dans l’histoire primordiale ». Études théologiques et religieuses Tome 98, no 2 (18 juillet 2023) : 165–76. http://dx.doi.org/10.3917/etr.982.0165.
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Michaela Bauks réfléchit sur le mal, un thème évoqué dans la Bible en même temps que la création du monde. Le récit biblique dit de la chute en Gn 2–3 traite certes d’une quête ambivalente de la connaissance du bien et du mal mais ne parle pas encore de péché, ni même de péché originel, comme cela est devenu un lieu commun depuis Augustin. En revanche, un terme hébreu pour « péché », ḥaṭṭaṯ , n’apparaît que dans le récit de Caïn et Abel (Gn 4). Ce concept ne signifie ni une faute concrète, ni un adversaire tel que le serpent ou le diable selon une conception dualiste, ni une attitude humaine. Le péché est plutôt la perversion de l’ordre de la vie qui devrait être orientée vers une justice connective. Il désigne une interférence dans l’ordre de la création et la conséquence de mauvais choix qui font échouer la cohabitation des humains.
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Rugo, Hope, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Antonino Musolino, Mark D. Pegram et al. « Abstract PD8-01 : Phase 3 SOPHIA study of margetuximab (M) + chemotherapy (CTX) vs trastuzumab (T) + CTX in patients (pts) with HER2+ metastatic breast cancer (MBC) after prior anti-HER2 therapies : Final overall survival (OS) analysis ». Cancer Research 82, no 4_Supplement (15 février 2022) : PD8–01—PD8–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd8-01.
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Abstract Background: CTX + dual HER2-targeting monoclonal antibodies (mAb) remains a standard of care for treatment (Tx) of both HER2+ early-stage and MBC. However, when the SOPHIA trial was launched, limited Tx options existed after progression on T, pertuzumab (P), and ado-trastuzumab emtansine. M, an Fc-engineered anti-HER2 mAb, targets the same epitope as T and exerts similar antiproliferative effects. M enhances CD16A-mediated ADCC compared to T. Furthermore, M treatment is associated with increased HER2-specific T- and B-cell responses and increased T-cell clonality compared to baseline. The phase 3 SOPHIA (NCT02492711) study demonstrated PFS benefit of M vs T, both + CTX, in HER2+ MBC pts. M improved PFS over T, with a 24% relative risk reduction (HR .76; 95% CI .59-.98; P=.033; median, 5.8 [95% CI 5.5-7.0] months (mo) vs 4.9 [95% CI 4.2-5.6] mo (Rugo HS, et al. JAMA Oncol 2021), resulting in FDA approval. Median OS after 270 mortality events (2nd interim analysis) was 21.6 mo with M vs 19.8 mo with T (HR .89; 95% CI .69-1.13; P=.33). Here we report final OS after 385 events, as well as updated safety.Methods: Pts with disease progression after ≥2 lines of anti-HER2 Tx, including P, and 1-3 lines of Tx for HER2+ MBC were randomized 1:1 to CTX + either M (15 mg/kg) or T (8 mg/kg loading dose, then 6 mg/kg), both given IV every 3 weeks. Randomization was stratified by number of metastatic sites (≤2, >2), lines of Tx for MBC (≤2, >2), and CTX choice (capecitabine, eribulin, gemcitabine, or vinorelbine). Sequential primary end points were central-blinded review of PFS and OS.Results: The intent-to-treat (ITT) population comprised 536 pts (M, 266; T, 270). At the median follow-up of 20.2 mo among all ITT pts, pts received a median of 7 cycles of M + CTX vs 6 cycles of T + CTX. Median OS after 385 events in the ITT population was 21.6 mo with M vs 21.9 mo with T (HR .95; 95% CI .77-1.17; P=.62; Table). Based on a prespecified, non-α-allocated exploratory analysis, a numerical OS advantage in favor of the M arm was observed in the subgroup of pts homozygous for the CD16A-158F low-affinity allele (median OS, 23.6 vs 19.2 mo; HR .72; 95% CI .52-1.00; nominal P=.05). In contrast, in the small subgroup of CD16A-158V homozygotes, median OS was longer for T vs M (31.1 mo vs 22.0 mo; HR 1.77; 95% CI 1.01-3.12; nominal P=.04). Grade ≥3 adverse events (AE) occurred in 146 pts (55.3%) receiving M vs 141 pts (53.0%) receiving T. Serious AEs were seen in 47 pts (17.8%) receiving M vs 51 pts (19.2%) receiving T. Incidence of infusion-related reactions was higher with M (36 [13.6%]) vs T (9 [3.4%]). Left ventricular dysfunction requiring delay or cessation of M/T administration occurred in 4 pts (1.5%) receiving M and in 7 pts (2.6%) receiving T. Conclusions: The median OS in the ITT population was not statistically different between the 2 arms. An exploratory analysis of CD16A genotyping indicates a numerical OS advantage in favor of M in F homozygous pts, along with a numerical OS advantage in favor of T in V homozygous pts. Safety of M + CTX was similar to previous reports and consistent with M FDA-approved label. Studies of M in HER2+ breast cancer pts with different CD16A allelic variants are warranted, including MARGOT, the neoadjuvant investigator-initiated study on the efficacy of M vs T in pts carrying F-allelic variants of CD16A. Median OSITT analysisPrespecified, non-α-allocated exploratory analysis (n=506)N=536CD16A-158F carriers (F/F and F/V)(n=437)CD16A-158F homozygotes (F/F)(n=192)CD16A-158F/V heterozygotes(n=245)CD16A-158V homozygotes (V/V)(n=69)aM + CTX, mo21.6 (n=266)23.3 (n=221)23.6 (n=102)21.3 (n=119)22.0 (n=37)T + CTX, mo21.9 (n=270)20.8 (n=216)19.2 (n=90)22.0 (n=126)31.1 (n=32)HR (95% CI)0.95 (0.77-1.17)0.86 (0.69-1.08)0.72 (0.52-1.00)0.96 (0.71-1.30)1.77 (1.01-3.12)P value0.620.19b0.05b0.78b0.04bAbbreviations: CTX, chemotherapy; HR, hazard ratio; ITT, intent to treat; M, margetuximab; mo, months; OS, overall survival; T, trastuzumab. Cutoff date: June 14, 2021. aThis subgroup was characterized by an imbalance in poor prognostic features. bNominal P value. Citation Format: Hope Rugo, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Antonino Musolino, Mark D. Pegram, Thomas Bachelot, Gail S. Wright, Cristina Saura, Santiago Escrivá-de-Romaní, Michelino De Laurentiis, Gary N. Schwartz, Timothy Pluard, Francesco Ricci, William Gwin, III, Christelle Levy, Ursa Brown-Glaberman, Jean-Marc Ferrero, Maaike de Boer, Sung-Bae Kim, Katarína Petráková, Denise A. Yardley, Orit Freedman, Erik H. Jakobsen, Einav Nili Gal-Yam, Rinat Yerushalmi, Peter A. Fasching, Emily Ashley, Shengyan Hong, Minori Rosales, William J. Gradishar. Phase 3 SOPHIA study of margetuximab (M) + chemotherapy (CTX) vs trastuzumab (T) + CTX in patients (pts) with HER2+ metastatic breast cancer (MBC) after prior anti-HER2 therapies: Final overall survival (OS) analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-01.
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Rossillo, Kim, Vivian Norman, Mary Wickman et Elizabeth Winokur. « Caritas Education : Theory to Practice ». International Journal for Human Caring 24, no 2 (1 juin 2020) : 106–20. http://dx.doi.org/10.20467/humancaring-d-19-00030.
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Increasingly complex occupational demands along with varied educational and personal examples of caring, may impact the ability to deeply connect with patients. Literature has identified that nurses and patients have differing perceptions of caring behaviors. Jean Watson's Theory of Human Caring provides a framework for care delivery that focuses on the caring nurse–patient relationship and the experience through the patients' lens.Caring healing relationships are at the core of professional nursing. The purpose of this project was to design and deliver an educational seminar based on Jean Watson's Theory of Human Caring to newly graduated nurses to examine the impact on self-efficacy in caring behaviors.The project participants (N = 56) consisted of a nonprobability convenience sample of newly graduated nurses at a local faith-based community hospital. The educational intervention consisted of experiential learning activities to facilitate translating theory to practice. The study utilized the Caring Efficacy Scale (CES), which is an instrument based on Watson's caring theory and Albert Bandura's self-efficacy theory. Results demonstrated a significant improvement in caring efficacy between the preintervention (M = 5.1, SD = .47), and immediate post intervention (M = 5.5, SD = .38); t (52) = −9.09, p = .000.The knowledge from this study could provide insights for the development of effective teaching strategies to facilitate translating nursing theory to practice. Establishing and developing skills to facilitate nurturing, caring nurse–patient relationships may enhance both the patient and caregiver experience.
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Luebbers, Thomas, Adrian Britschgi, Veronica Costa, Thomas Friess, Jean-Christophe Hau, Gordon Heidkamp, Holger Kuehne et al. « Abstract 5769 : Target identification of T-cell activating immunomodulatory tetrahydrothiazepines : DGKα and DGKζ inhibitors ». Cancer Research 84, no 6_Supplement (22 mars 2024) : 5769. http://dx.doi.org/10.1158/1538-7445.am2024-5769.
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Abstract We became interested in bicyclic tetrahydrothiazepine derivatives described in a Patent (WO 2016/139181) having immunomodulatory activities on CD3-activated T cells (CD4+ & CD8+) and NK cell increasing the secretion of several cytokines such as, e.g., IL-2, IFN-γ and/or TNF-α whereas corresponding unstimulated immune cells do not respond. Surprisingly - in contrast to what has been described in the patent - the N-H of the Amides 1 and 2 described in the patent was not required for potency and the oxadiazoles 1 and 2 were significantly more potent in T-cell proliferation and IL-2 release. Compound 1 was in vivo active in a single dose PD study in mice after CD3 activation and in a MC38 xenograft mice model showing single agent activity. Amide 1 and Amide 2 were identified in a phenotypic screen and the mode of action was unknown. Because of the promising pharmacological profile and in vivo activity, we were interested in the target. Here we describe how we identified the potential targets DGKα and DGKζ. Citation Format: Thomas Luebbers, Adrian Britschgi, Veronica Costa, Thomas Friess, Jean-Christophe Hau, Gordon Heidkamp, Holger Kuehne, Laetitia J. Martin, Filip Roudnicky, Manuel Tzouros, An Vandemeulebroucke. Target identification of T-cell activating immunomodulatory tetrahydrothiazepines: DGKα and DGKζ inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5769.
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Pichette, Jean-Pierre. « Gerald THOMAS, The Two Traditions. The Art of Storytelling Amongst French Newfoundlanders, (Saint-Jean (T.-N.), Breakwater, « Canada’s Atlantic Folklore-Folklife Series », 1993, 379 pages.) ». Ethnologies 17, no 1 (1995) : 205. http://dx.doi.org/10.7202/1087477ar.
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Fabre, Éric. « Jean-Luc Pontvieux et Daniel Llinarès (dir.), Congénies en Vaunage , Association Maurice Aliger, coll. « Monographies vaunageoles », n° 6, 2016, 1 104 p., 3 t., 30 €. » Histoire & ; Sociétés Rurales Vol. 47, no 1 (3 juillet 2017) : XXII. http://dx.doi.org/10.3917/hsr.047.0181v.
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Hillson, Lily V., Ross K. McMahon, Kathryn A. Pennel, Jean A. Quinn, Leia Jones, Raheleh Amirkhah, Aula Ammar et al. « Abstract 3231 : Temporal changes in intratumoral and systemic lymphocytes in response to short and long course radiotherapy regimens in locally advanced rectal cancer ». Cancer Research 83, no 7_Supplement (4 avril 2023) : 3231. http://dx.doi.org/10.1158/1538-7445.am2023-3231.
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Abstract Background. Two pre-operative radiotherapy (RT) regimens are in common use for patients (pts) with locally advanced rectal cancer (LARC): Conventionally fractionated, long course chemoradiation (LCCRT, 25x1.8Gy with concomitant chemotherapy) or hypofractionated short-course RT (5X5Gy) followed by systemic chemotherapy (SCRT-C). RT is thought to induce immune responses to cellular damage, but the understanding of their evolution and relation to fractionation is limited. We are conducting a serial biospecimen collection in such pts with baseline, 2, 6 and 12 week (wk) sampling. We report serial measurement of tumor and peripheral blood lymphocyte responses for each regimen. Method. Multiplex immunofluorescence quantified tumor infiltrating lymphocytes (CD8, FOXP3). Routine diagnostic flow cytometry quantified circulating lymphocytes. A multiplex ELISA quantified cytokines in blood plasma. Bulk RNA-sequencing (QuantSeq) quantified gene expression within the tumor. Result. We report results for 20pts who received RT for stage III/IV LARC (13 LCCRT, 7 SCRT-C). Biopsy results are available for 10pts, circulating lymphocytes for 20pts and peripheral blood cytokines for 16pts. In LCCRT patients (n=8), relative to baseline, tumor infiltrating cytotoxic (CD8+) T cells were uniformly decreased during (2wks, P<0.05) and directly after treatment (6wks, P<0.05) before returning to baseline at 12wks. T regulatory cells (FOXP3+) similarly significantly decreased at 2wks and 6wks but remained below baseline at 12wks (P<0.05). Circulating lymphocytes also fell at wk2 and wk6 after commencing LCCRT and had begun recovering by wk12(n=13; P<0.05). The concentrations of circulating interleukins secreted by (IL2, IL8) or which activate T-lymphocytes (IL2, IL15) were reduced in the circulation at wk2 (n= 9; P<0.05) and wk6 (NS). In SCRT-C patients, we noted an increase in CD8 T cells at 2wks in 2/2 pts, also reflected in gene expression data, and an increase in FOXP3 T cells in 1/2 pts. Circulating lymphocytes were similarly decreased at wk2 in both the SCRT-C (n=7) and LCCRT (n=13) pts, but this reduction was less marked within the SCRT-C cohort at wk6 (P<0.01) and wk12 (P<0.05) relative to LCCRT patients. IL2, IL8 and IL15 did not change during or after SCRT-C (n=7; NS). Conclusion. LCCRT caused a drop in T cells during treatment, whilst SCRT-C appears to induce intra-tumoral T cell responses from wk2 and abrogates systemic reactions to a lesser extent. These results require evaluation in a larger cohort but have implications for understanding how RT induces microenvironmental changes and impacts pelvic bone marrow. We show in vivo that SCRT may be more immunostimulatory in LARC, with implications for trials combining RT with immunotherapy. Citation Format: Lily V. Hillson, Ross K. McMahon, Kathryn A. Pennel, Jean A. Quinn, Leia Jones, Raheleh Amirkhah, Aula Ammar, Phimmada Hatthakarnkul, Annabelle Ferguson, Simon W. Milling, Alec McDonald, Philip D. Dunne, Joanne Edwards, Sean M. O'Cathail, Campbell S. Roxburgh. Temporal changes in intratumoral and systemic lymphocytes in response to short and long course radiotherapy regimens in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3231.
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Kikuchi, Shota, Piergiorgio Pettazzoni, Kristen A. Baltgalvis, Kelsey N. Lamb, Kent T. Symons, Chu-Chiao Wu, Melissa A. Hoffman et al. « Abstract ND11 : Chemoproteomic-enabled discovery of VVD-214, a synthetic lethal allosteric inhibitor of WRN helicase ». Cancer Research 84, no 7_Supplement (5 avril 2024) : ND11. http://dx.doi.org/10.1158/1538-7445.am2024-nd11.
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Abstract WRN helicase is a promising target for treating cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms. Currently, there are no approved drugs directly targeting human DNA or RNA helicases, in part due to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemical proteomic-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN. The clinical lead, VVD-214, covalently engages cysteine 727 of WRN in a nucleotide cooperative manner and inhibits ATP hydrolysis and helicase activity, resulting in widespread double-stranded DNA breaks, nuclear swelling, and cell death in MSI-high, but not microsatellite stable cells. VVD-214 provided robust tumor regression in multiple MSI-high colorectal cancer cell lines and patient derived xenograft models, including models derived from patients progressing on immune checkpoint therapies. VVD-214 was exceptionally well tolerated, and constitutes a promising oral drug candidate for patients with MSI-high cancers. Citation Format: Shota Kikuchi, Piergiorgio Pettazzoni, Kristen A. Baltgalvis, Kelsey N. Lamb, Kent T. Symons, Chu-Chiao Wu, Melissa A. Hoffman, Aaron N. Snead, Xiaodan Song, Thomas Glaza, Jason C. Green, Donald C. Rogness, Betty Lam, Maria E. Rodriguez-Aguirre, David R. Woody, Christie L. Eissler, Socorro Rodiles, Seth M. Negron, Steffen M. Bernard, Eileen Tran, Jonathan Pollock, Ali Tabatabaei, Victor Contreras, Heather N. Williams, Martha K. Pastuszka, John J. Sigler, Markus G. Rudolph, Moritz Classen, Doris Brugger, Christopher Claiborne, Jean-Marc Plancher, Isabel Cuartas, Joan Seoane, Laurence E. Burgess, Robert T. Abraham, David S. Weinstein, Gabriel M. Simon, Matthew P. Patricelli, Todd M. Kinsella. Chemoproteomic-enabled discovery of VVD-214, a synthetic lethal allosteric inhibitor of WRN helicase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND11.
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Stankovic, Vlada. « Tropeoforos kod Mihaila Psela - jedan primer politicke upotrebe retorike ». Zbornik radova Vizantoloskog instituta, no 41 (2004) : 133–51. http://dx.doi.org/10.2298/zrvi0441133s.
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(francuski) En raison de sa grande ?rudition, de son talent litt?raire, mais aussi de son caract?re, Michel Psellos est assur?ment un des auteurs byzantins les plus probl?matiques lorsqu'il s'agit de l'interpr?tation et de la compr?hension de ses oeuvres. Le recours ? l'allusion, surtout dans ses ?crits politiques, r?v?le chez un auteur imbu de son savoir le besoin de jouer avec la signification ?officielle?, claire et compr?hensible de tous de ses textes, et une seconde plus profonde en recourant ? des images ?sot?riques, absconses ou difficilement compr?hensibles. Il en est ainsi s'agissant de l'emploi de l'?pith?te tropaiophoros (tropaioph?roz) que Michel Psellos utilise de fa?on sp?cifique, en jouant avec sa signification principale et concr?te. 1. L'emploi du qualificatif tropaiophoros (tropaioph?roz) chez Psellos 1.1. L'?loge ? Constantin Monomaque (Psellus, Orationes, Oratio 2) L'?loge ? Constantin Monomaque r?dig? par Psellos au d?but m?me du r?gne de cet empereur (avril-mai 1043) est caract?ristique lorsqu'il s'agit de l'utilisation du terme tropaiophoros par Psellos. C?l?brant la victoire de l'empereur sur l'usurpateur Georges Maniak?s, Michel Psellos a r?ussi par l'habile emploi de cette ?pith?te ronflante ? qui ? cette ?poque ?tait avant tout utilis?e pour d?signer la fondation de Constantin Monomaque, Saint-Georges Tropaiophoros ? Manganes ? d'exprimer, par le biais de l'ironie, son opinion critique vis-?-vis du nouvel empereur. Proc?dant ? un rappel de l'histoire de Byzance depuis la mort de Jean Tzimisk?s (976) jusqu'? la r?daction de son ?loge, Michel Psellos utilise ? trois reprises l'?pith?te tropaiophoros : 1) associ?e ? Michel IV le Paphlagonien : ...le tropaio- phoros c?leste (immacul?) retourne ? son seigneur, c.-?-d. ? Dieu (ka? tropaioph?roz ana?maktoz pr?z t?n o?ke?on desp?t?n ch?rei ?e??????? x^pei) ; 2) ? Constantin Monomaque : ...et avant le sceptre tu ?tais empereur tropaiophoros (ka? pr? t?n sk?ptr?n basile?z ?stha tropaioph?roz ??o??a????o?) ; 3) et ? l'usurpateur d?fait qui s'?tait dress? contre cet empereur, Georges Maniak?s (symb?llei t? t?z d?se?z strat?g?, nik?, tropaioph?roz ?p?neisi, sobar?teroz t? e?tych?mati g?netai?). Son habile r?partition du terme tropaiophoros dans trois passages ?galement ?loign?s les uns des autres, respectivement dans le premier, deuxi?me et troisi?me tiers de la partie historique de son oratio, met tout particuli?rement en exergue l'importance de ce qualificatif. En tant qu'id?e, la notion de tropaiophoros est sous-jacente ? tout le cours narratif de cet ?loge, constituant d'une certaine fa?on le fondement sur lequel l'orateur a construit et ?labor? son r?cit. Le choix des personnages auxquels Psellos associe l'?pith?te tropaiophoros et les diverses nuances qu'elle rev?t avec chacun d'eux, renforcent l'impression d'un emploi intentionnel d'un terme inhabituel, visant par l? ? transmettre un message politique. Tout d'abord, l'?pith?te tropaiophoros est utilis?e exclusivement pour des personnages contemporains dont le nouvel empereur Constantin Monomaque qu'un lien particulier rattache aux deux autres ? ces deux derniers ayant ?t?, en quelque sorte, l'un comme l'autre ses adversaires, et tous deux l'ayant, du moins provisoirement, d?fait. Autrement dit, seuls les rivaux de Monomaque sont, tout comme lui, qualifi?s de tropaiophoros, alors que ni Basile II, ni Romain Argyre, auquel Psellos dresse des louanges particuli?res dans le cadre de cet ?loge, n'ont re?u cette ?pith?te. Le fait que Michel Psellos ait renonc? par la suite ? utiliser l'?pith?te tropaiophoros dans ses ?loges post?rieurs de Constantin Monomaque et n'ait renou? pleinement avec son emploi qu'apr?s le r?gne de cet empereur, lorsque le temps ?coul? avait ?t? toute actualit? politique ? ce terme, atteste peut-?tre une dose redoubl?e de prudence (voire de crainte?) de la part de cet ?rudit qui redoutait que ne soient d?crypt?es ses allusions et critiques politiques d?guis?es sous formes d'?loges. 1.2. La Chronographie et autres oeuvres de Psellos Le choix m?me des personnages s'?tant vu attribuer l'?pith?te de tropaiophoros dans la Chronographie est d?j? significatif par lui-m?me (Bardas Phocas, Constantin Monomaque, Isaac Comn?ne, Romain Diog?ne et Andronic Doukas, fils du c?sar Jean Doukas), mais Psellos a ?galement exprim? ses positions vis ? vis de ceux-ci ? travers les nuances introduite dans l'emploi de cette ?pith?te avec chacun d'entre eux. Passant de l'ironie non dissimul?e (dans le cas de Romain Diog?ne) ? la moquerie d?guis?e (Andronic Doukas), Psellos joue avec la signification premi?re de l'?pith?te tropaiophoros et ce d'une fa?on qui n'est pas pleinement apparue ? des ?rudits tels que Nic?phore Bryennios et Anne Comn?ne lesquels, proc?dant ? la copie des donn?es fourmes par Psellos, ont repris tel quel ce terme. La possibilit? de l'emploi ambivalent de l'adjectif tropaiophoros nous sont r?v?l?s par Psellos lui-m?me dans sa description de l'empereur H?raclius dans le Logos sur les miracles de l'archange Michel, lorsqu'il dit de cet empereur qu'il ?tait un authentique tropaiophoros (tropaioph?roz ?z ?l?th?z), formule que l'on ne retrouve pour aucun de ses contemporains. 2. Caract?risation de l'emploi du terme tropaiophoros chez Psellos La caract?risation de l'emploi de l'?pith?te tropaiophoros par Psellos, tout en gardant la r?serve qui s'impose, montre que le consul des philosophes a intentionnellement utilis? cette ?pith?te, l'a introduite ? des endroits parfaitement bien choisis et attribu?e ? des personnages bien pr?cis tout en lui conf?rant le plus souvent une connotation ironique. Deux exemples relev?s dans l'?loge de Constantin Monomaque montrent parfaitement que tropaiophoros pouvait ?tre utilis? avec une double signification, ? officielle? (positive) mais aussi ? dissimul?e ? (cachant une critique). L'empereur lui-m?me, alors qu'il n'y va d'aucun m?rite particulier de sa part, et avant m?me de recevoir la couronne imp?riale, est tropaiophoros, qualificatif ? travers lequel Psellos fait, de toute ?vidence, allusion ? l'?rection contemporaine de la fondation du m?me nom de Monomaque, d'une fa?on que l'empereur lui-m?me pouvait comprendre, approuver et r?compenser. Toutefois, l'exemple de Michel IV tir? de ce m?me oratio, montre un autre aspect de l'utilisation de cette ?pith?te ? cet empereur est, en effet, tropaioph?roz ?na?maktoz, ce qui l'?l?ve au-dessus de Monomaque auquel l'?loge est destin?. C'est l? une position conforme ? l'opinion g?n?rale positive de Psellos sur Michel le Paphlagonien que l'on retrouve ?galement exprim?e dans la Chronographie. Dans tous les autres cas ? ? l'exception de celui de l'empereur H?raclius ? une connotation ironique dissimul?e ou un ton moqueur annonce les intentions de l'auteur, en particulier du fait du contraste que Psellos cr?? en attribuant l'?pith?te tropaiophoros ? des empereurs y compris lorqu'il n'y a pas eu de v?ritables victoires. L'?pith?te li?e ? saint Georges, et le plus souvent associ?e dans la rh?torique byzantine ? un empereur ? victorieux a ?t? utilis? par Psellos pour jouer avec sa signification premi?re, mais aussi afin de traduire un message associ? ? son utilisation. 3. Saint Georges Tropaiophoros ? Manganes L'emploi appuy? de l'?pith?te tropaiophoros par Psellos dans son ?loge r?dig? au d?but du r?gne de Constantin Monomaque (avril ? mai 1043) confirme indubitablement que la construction de la fondation de Monomaque ?tait alors commenc?e, 151 mais aussi qu'elle portait d?j? l'?pith?te de tropaiophoros. En outre, le sceau de Skl?raina sur lequel est ?galement mentionn? le sekret?n du saint grand martyr Georges Tropaiophoros, puis l'existence du monast?re du Tropaiophoros avant le mois de mai 1046 (sur la base de la charte de Constantin Monomaque), ainsi que le caract?re et les appellations des ?loges de Mauropous, montrent que l'?glise de Saint-Georges Tropaiophoros a ?t? inaugur?e plus t?t qu'on ne le pensait jusqu'? pr?sent. L'absence de toute description de la nouvelle ?glise, de ses d?corations ou de son luxe dans les r?cits de Jean Mauropous, ce qui ?tait habituel pour les hom?lies qui c?l?braient la sanctification des ?glises depuis l'?poque de patriarche Photius, incite ? conclure qu'il ne s'agissait pas dans ce cas d'un acte aussi solennel. Les imges usuelles et neutres employ?es par Mauropous pour louer les fondations de l'empereur, tel que saint Sion et nouvelle J?rusalem ou la mention stipulant que l'?glise surpassait les autres ?glises par sa taille et ses d?corations, ne doivent en aucun cas ?tre rattach?es avec la c?r?monie de sanctification de l'?glise qui, ? ce qu'il semble, a eu lieu avant mai 1046, et certainement avant le 21 avril 1047 lorsque Jean Mauropous y a prononc? l'?loge de son fondateur, l'empereur Constantin Monomaque.
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Kocoglu, Mehmet, Aaron P. Rapoport, Etse Gebru, Destiny Omili, Daniel Yamoah, Rediet Mulatu, Jean Yared et al. « Abstract 3616 : In vivo expansion patterns of anti-BCMA CAR T-cell in relapsed/refractory multiple myeloma : Comparative immunomonitoring of idecabtagene vicleucel and ciltacabtagene autoleucel ». Cancer Research 84, no 6_Supplement (22 mars 2024) : 3616. http://dx.doi.org/10.1158/1538-7445.am2024-3616.
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Abstract Introduction: Chimeric antigen receptor (CAR) T cell (CAR-T) treatments have revolutionized the treatment of multiple myeloma (MM). Two CAR-T cell products targeting B cell maturation antigen (BCMA) have received approval for the treatment of MM: idecabtagene vicleucel (idecel) and ciltacabtagene autoleucel (ciltacel). A comparative analysis of in vivo CAR-T responses in patients receiving these novel cellular therapies has not been performed, especially not in the real-world setting. Methods: We prospectively enrolled 23 MM patients treated with idecel or ciltacel in our study GCCC2043. Blood samples were obtained at apheresis, pre-lymphodepleting (LD) chemotherapy, on days 0, +7, +14, +21, +28 and at +3 months post CAR-T. Samples were stained using BCMA or control CAR detection reagents, monoclonal antibodies against T cell surface antigens, and analyzed using flow cytometry. Results: Baseline clinical characteristics, pre-apheresis and pre-LD absolute lymphocyte counts were comparable between groups. There were no G3 cytokine release syndrome (CRS) events whereas G1/2 CRS and all-grade Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) events were not significantly different between cohorts. The global overall response rate (ORR) was 78.3% (n=18) and 60.9% (n=14) at days 30 and 90, respectively. At +1 month, 72.7% (8/11) of idecel and 83.3% (10/12) of ciltacel cohort had an objective response (p=0.625). There was no statistical ORR difference between idecel and ciltacel cohorts at 3, 6, and 9 months. Two-way ANOVA of CAR-T expansion studies revealed a trend towards an effect of treatment type (p=0.0595). Time to peak CAR-T numbers was significantly shorter for idecel (p=0.0127), however, ciltacel showed a significantly more pronounced CAR-T expansion (p=0.043) and longer persistence. Peak CAR-T expansion was associated with clinical responses across cohorts at +1 (p=0.034) and +3 months (p=0.050). Day +30 responses were indicative of Day +90 and Day +180 responses (p<0.001, p=0.011). There was no difference in CD8+ CAR T cell peak levels, however, CD4+ CAR T cell peak levels were much higher (p=0.019) for ciltacel vs. idecel. Similarly, there were significantly higher (p=0.002) CD4+/CD8+ double-positive CAR-T peak levels in ciltacel vs. idecel patients. There was no significant difference in the distribution of T cell memory subtypes at peak level. Conclusions: We demonstrate here for the first time significant differences in CAR T cell expansion and persistence patterns following infusion of either idacel or ciltacel. Studies are underway at our institution investigating anti-BCMA CAR T cell responses in more detail and larger numbers of patients. Such studies have the potential to identify predictive/prognostic biomarkers and/or lead to further optimization of myeloma-targeting CAR-T. Citation Format: Mehmet Kocoglu, Aaron P. Rapoport, Etse Gebru, Destiny Omili, Daniel Yamoah, Rediet Mulatu, Jean Yared, Nancy M. Hardy, Michael Kallen, Ashraf Z. Badros, Djordje Atanackovic. In vivo expansion patterns of anti-BCMA CAR T-cell in relapsed/refractory multiple myeloma: Comparative immunomonitoring of idecabtagene vicleucel and ciltacabtagene autoleucel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3616.
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Behl, Deepti, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Niklas Mackler, Herbert L. Duvivier, Philip J. Gold et al. « Abstract CT267 : Temsirolimus (T) in patients (pts) with solid tumors with AKT1/3 amplification (amp) or mutation (mut) : Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study ». Cancer Research 84, no 7_Supplement (5 avril 2024) : CT267. http://dx.doi.org/10.1158/1538-7445.am2024-ct267.
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Abstract Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with AKT1/3 amp or mut treated with T are reported. Methods: Eligible pts had solid tumors, measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. After antihistamine pretreatment, 25 mg T was infused over 30-60 minutes once weekly until disease progression. Low accruing histology-specific cohorts with AKT1/3 amp or mut were collapsed into 1 histology-pooled cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete or partial response or stable disease (SD) of at least 16 weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test with α= 0.10. Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of SD, and safety. Results: 28 pts with solid tumors (14 tumor types; 13 pts had breast, ovarian or endometrial tumors) with AKT1 mut (n=25), AKT1 amp (n=1), both AKT1 amp and mut (n=1), or AKT3 amp (n=1) were enrolled. All pts were evaluable for efficacy. Table shows demographics, outcomes and toxicity. 4 pts with SD16+ (lung, breast, endometrial and ossifying fibromyxoid tumor) were observed for a DC rate of 14% (1-sided 90% CI: 6 to 100) and an OR rate of 0% (95% CI: 0 to 12). The null DC rate was not rejected (p=0.62). All 4 pts with DC had an AKT1 E17K mut. 5 pts had ≥1 grade 3 adverse events (AE) or serious AEs (SAE) at least possibly related to T. Conclusions: T did not meet TAPUR’s prespecified criteria to declare a signal of activity in pts with solid tumors with AKT1/3 mut or amp. Table 1. Demographics, Efficacy Outcomes, and Toxicity Outcomes (N=28) Median (Med) age, years (range) 66 (39-83) Female, No. (%) 22 (79) ECOG PS, No. (%) 0 12 (43) 1 12 (43) 2 4 (14) Prior systemic regimens, No. (%) 1 2 (7) 2 6 (21) ≥3 20 (71) DC rate, % (OR and SD16+) (1-sided 90% CI) 14 (6, 100) OR rate, % (95% CI) 0 (0, 12) Med PFS, wks (95% CI) 8 (6, 8) Med OS, wks (95% CI) 25 (14, 31) Med duration SD for patients with SD16+ (range), wks (n=4) 26 (18, 40) Number of pts2 (%) with tx-related AE or SAE (all grade 3) AE3 5 (18) SAE4 3 (11) 1 Percentages may be >100% due to rounding2 Pts may have experienced one or more events3 Lymphocyte count decrease and oral mucositis4 Anorexia, fatigue, pericardial effusion, thromboembolic event Citation Format: Deepti Behl, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Niklas Mackler, Herbert L. Duvivier, Philip J. Gold, Sapna R. Patel, Regan M. Duffy, Lauren A. Mauro, Eugene R. Ahn, Maria Bell, Carmen J. Calfa, Jean L. Grem, Jens Rueter, Margaret von Mehren, Gina N. Grantham, Abigail Gregory, Dominique C. Hinshaw, Susan Halabi, Richard L. Schilsky. Temsirolimus (T) in patients (pts) with solid tumors with AKT1/3 amplification (amp) or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT267.
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Kabraji, Sheheryar, Jing Ni, Sarah Sammons, Amanda ED Van Swearingen, Yanzhi Wang, Alyssa M. Pereslete, Liangge Hsu et al. « Abstract PD4-05 : Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases (BCBM) ». Cancer Research 82, no 4_Supplement (15 février 2022) : PD4–05—PD4–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd4-05.
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Abstract Purpose: Up to half of patients (pts) with HER2+ metastatic breast cancer (MBC) will develop BCBM. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) with demonstrated efficacy in previously treated pts with HER2+ MBC. However, few pts with stable/treated brain metastases, and no pts with active (untreated or progressive) brain metastases, were included in completed clinical trials of T-DXd. Thus, central nervous system (CNS) efficacy of T-DXd is not well-characterized. Methods: We tested T-DXd in orthotopic pt BCBM-derived xenograft (PDX) models of HER2+, and HER2-low, BCBMs. To further validate T-DXd single agent CNS activity, we described clinical outcomes of T-DXd in a multi-institutional retrospective cohort of 16 patients with BCBM. Consecutive pts who initiated T-DXd between 1 Jan 2020 - 1 Nov 2020 (Duke) or 1 Jan 2020 - 15 June 2020 (Dana-Farber Cancer Institute) were included. Data cut-off date was 31 Dec 2020. CNS response was measured by via central radiology review at each participating institution. Up to 5 CNS target lesions were included. CNS partial response (PR) required >30% reduction in sum of CNS target lesions. Results: Treatment with 10 mg/kg T-DXd significantly prolonged survival in HER2+ BCBM PDX models DFBM-354 (67 vs 154 days, p=0.0018) and DFBM-355 (78 vs 156 days, p=0.0067) vs. vehicle control. We then tested TDX-d in a HER2 low BCBM PDX model (IHC 2+/FISH ratio <2) and found that c.f. vehicle, TDX-d significantly prolonged survival (72 v 141 days, p = 0.02). Finally, we treated DFBM-355 with trastuzumab emtansine (T-DM1) to generate resistance followed by treatment with T-DXd. We found that c.f. vehicle or continued T-DM1, T-DXd significantly prolonged survival in a T-DM1 resistant BCBM PDX model (63 vs 99 vs 215 days, p=0.01). In the retrospective cohort, median age was 44 (33-69 years). 15/16 pts had confirmed HER2 IHC 3+ or FISH-positive primary or metastatic tissue. 9/16 (56%) pts had either progressive or untreated HER2+ BCBMs on initiation of T-DXd. Median number of prior metastatic therapies was 4 (0-10). 14/16 (88%) had received previous T-DM1; 11/16 (69%) had received previous HER2-targeted tyrosine kinase inhibitor. Median time from previous CNS radiation was 15.1 months (1.3 - 45.2). At the time of data cutoff, 7 pts remained on T-DXd. Median number of cycles was 7 (2-17+). Responses are shown in Table 1. The overall intracranial clinical benefit rate (CR/PR or stable disease) was 75%, including 89% (8/9) of those with progressive or untreated BCBM at baseline. Conclusions: In a multi-institution cohort of 16 pts with HER2+ BCBMs treated with T-DXd, we find preliminary evidence of CNS efficacy, including in pts with progressive or untreated BCBMs. Additional pt data and further follow up will be presented at the meeting. Using BCBM PDX models we find that T-DXd prolongs survival in untreated HER2+ BCBM PDX models as well as in T-DM1 treated models. We also demonstrate efficacy of T-DXd in a HER2 low BCBM PDX model. Together, these data suggest that T-DXd has intracranial efficacy against HER2+ BCBMs. Prospective clinical trials in this pt population are warranted. Table 1.Best CNS Response of study cohortOverall population (n=16)Pts with progressive or untreated CNS disease at baseline (N=9)Pts with stable/treated CNS disease at baseline (N=7)Complete response (CR)0 (0)00 (0)Partial response (PR)10 (63)6 (67)#4 (57)+Stable disease (SD)2 (13)2 (22)0 (0)Progressive disease (PD)1 (6)0 (0)1 (14)No measurable CNS disease at baseline2 (13)0 (0)2 (29)Lost to follow-up1 (6)1 (11)0 (0).#Among these 6 pts, interval between most recent radiation and T-DXd initiation was 14.3 months, 12.4 months, 17 months, 18.2 months, and 8.2 months (one pt was radiation-naïve). +Among these 4 pts, interval between most recent radiation and T-DXd initiation was 19.1 months, 15.1 months, 1.5 months, and 16.9 months, respectively. Citation Format: Sheheryar Kabraji, Jing Ni, Sarah Sammons, Amanda ED Van Swearingen, Yanzhi Wang, Alyssa M Pereslete, Liangge Hsu, Chris Lascola, Heather Moore, Melissa Hughes, Akshara S Raghavendra, Maria Gule-Monroe, Rashmi K Murthy, Eric P Winer, Carey K Anders, Jean J Zhao, Nancy U Lin. Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases (BCBM) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-05.
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Gombis, Timothy G. « Kevin J. Vanhoozer, Craig G. Bartholomew, Daniel J. Treier and N. T. Wright (eds), Dictionary for Theological Interpretation of the Bible (Grand Rapids, MI and London : Baker Academic/SPCK, 2005), pp. 896. $49.99. » Scottish Journal of Theology 62, no 2 (mai 2009) : 228–29. http://dx.doi.org/10.1017/s0036930606002390.
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Wang, Tianjiao, Jean-Marc Navenot, Stavros Rafail, Mark Carroll, Ruoxi Wang, Cheryl McAlpine, Swethajit Biswas et al. « Abstract LB001 : Identifying MAGE-A4-positive tumors for SPEAR T-cell therapies in HLA-A*02-eligible patients ». Cancer Research 82, no 12_Supplement (15 juin 2022) : LB001. http://dx.doi.org/10.1158/1538-7445.am2022-lb001.
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Abstract Autologous T-cells engineered with T-cell receptors (TCRs) targeting tumor antigens are promising therapies for metastatic solid cancers.1 Specific peptide enhanced affinity receptor (SPEAR) T-cell therapies are T-cells with engineered HLA-restricted TCRs that precisely target tumor cells with specific antigens, such as MAGE-A4 (a cancer testis antigen), presented on the surface by HLA molecules. In SPEAR T-cell clinical trials targeting MAGE-A4, a 2-step prescreen is done before enrolment. 1) Patients undergo HLA typing via a high-resolution (allelic, 4-digit) sequence-based assay, and those who are positive for the inclusion alleles (HLA-A*02:01P, 02:02P, 02:03P, 02:06P) and not positive for the exclusion allele A*02:05P are eligible. 2) Tumor MAGE-A4 testing is done via an immunohistochemical clinical trial assay (MAGE-A4+ cutoff: ≥30% tumor cell staining at ≥2+ intensity) in HLA-eligible patients. A screening protocol (NCT02636855) has been used in Phase 1 trials of first- and next-generation SPEAR T-cells targeting MAGE-A4 (NCT03132922, NCT04044859) with responses in multiple MAGE-A4+ tumors. As of November 19, 2021, 6,168 patients with 9 solid tumor types were screened at 32 sites across North America and Europe in this screening protocol; among which, 2,744 were HLA-eligible (eligibility rate: 45%, range per tumor type: 42%-55%). HLA-A*02:01 was the most frequent HLA-A*02 allele. Of these HLA-eligible patients, 1,549 had tumor tissues evaluable for MAGE-A4 expression; among which, 313 were MAGE-A4+ (MAGE-A4+ rate: 20%, range: 8%-54%) (Table). MAGE-A4 showed highest prevalence in synovial sarcoma and myxoid/round cell liposarcoma but was seen across all tumor types investigated. Our results will be discussed in the context of tumor histopathology, disease status, and demography. HLA and MAGE-A4 biomarker data will inform the therapeutic opportunities for SPEAR T-cells targeting MAGE-A4 in metastatic solid cancers. 1. D’Angelo et al. Cancer Discov. 2018;8:944. HLA eligibility and MAGE-A4 prevalence in a screening protocol (NCT02636855) Indication Esophageal cancer Esophagogastric junction cancer Gastric cancer Head and neck squamous cell carcinoma Non-small cell lung cancer Melanoma Ovarian cancer Urothelial cancer Synovial sarcoma and myxoid/round cell liposarcoma HLA screened (N) 284 228 271 601 3189 668 539 270 118 HLA eligible (%) 46 45 43 42 43 50 49 43 55 MAGE-A4 evaluable (N) 104 91 73 200 457 245 225 93 61 MAGE-A4 positive (%) 22 25 8 22 14 16 24 32 54 Citation Format: Tianjiao Wang, Jean-Marc Navenot, Stavros Rafail, Mark Carroll, Ruoxi Wang, Cheryl McAlpine, Swethajit Biswas, Francine Brophy, Erica Elefant, Paige Bayer, Sandra McGuigan, Dennis Williams, George Blumenschein, Marcus Butler, Jeffrey M. Clarke, Justin F. Gainor, Ramaswamy Govindan, Victor Moreno, Janet Tu, David S. Hong. Identifying MAGE-A4-positive tumors for SPEAR T-cell therapies in HLA-A*02-eligible patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB001.
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Sorochinsky, Gleb Romanovich. « Semantics and Function of Stelae in the Ancient Architecture of the Near East in the Era from the Neolithic Man to the Epic Gilgamesh and the Biblical Jacob ». Культура и искусство, no 8 (août 2023) : 74–85. http://dx.doi.org/10.7256/2454-0625.2023.8.39760.
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The subject of the study is such a phenomenon in the cult architecture of the Near East region (Levant, Mesopotamia, Anatolia, Elam) as the erection of stelae. Special attention is paid to the semantics of stelae, which had a sacred meaning for ancient people. The purpose of the research is to identify the main functions and meanings characteristic of such a typological unit in the architecture of the Near East as the stela (stele). The relevance of the research is determined by the development of interdisciplinary discourse in this issue among domestic (N. Ya. Merpet, E. V. Antonova, A. B. Zubov, T. V. Kornienko, V. V. Emelianov) and foreign (J. Mellaart, K. Schmidt) scientists. The scientific research of the article is based on the architectural-ontological research method: analysis of architectural objects (Göbekli Tepe, Nevali Çori) with the identification of typological and compositional features, analysis of literary sources in the form of sacred texts (the Epic of Gilgamesh, the Bible) with the identification of the semantic field of meanings. The novelty of the study is determined by the identification of the architectural and ontological role of stelae in the ancient architecture of the region. As a result of the study, a number of basic semantic meanings and functions characteristic of such a typological unit in the architectural tradition of the Near East as the stela (stele) are given. These conclusions can be applied in such areas of the humanities as history, philosophy, cultural studies, religious studies, art history, architecture, archeology and other sciences.
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Peyraud, Florent, Jean-Philippe Guegan, Christophe Rey, Marina Pulido, Emmanuelle Bompas, Sophie Piperno-Neumann, Christine Chevreau et al. « Abstract 2578 : High regulatory T cells infiltrate within tertiary lymphoid structure restricts response to immune checkpoint blockers in sarcomas ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 2578. http://dx.doi.org/10.1158/1538-7445.am2022-2578.
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Abstract Background: While composition of the tumor microenvironment (TME) is a prerequisite for an effective antitumor immunity, infiltration of organized B- and T-cells aggregates called tertiary lymphoid structures (TLS) has been recently demonstrated to predict response to immune checkpoint blockers (ICB) in sarcomas. However, only a minority of patient derive benefit, suggesting the implication of additional key determinants of ICB-mediated response in TLS-positive sarcomas, such as TLS composition. Using high-throughput spatial transcriptomics and multiplex immunofluorescence (IHF), we aimed at investigating the association between TLS composition and clinical outcome to ICB. Methods: In an exploratory cohort, we spatially profiled the expression of more than 18000-protein encoding genes from responders (R) and non-responders (NR) using Nanostring’s GeoMx Digital Spatial Profiler (DSP) Whole Transcriptome Atlas (WTA) assay. A first set of regions of interest (ROI) was selected in the TLS and further segmented in “B-cells” vs “no B-cells” areas according to CD20+ staining; a second set of ROI was selected in the tumor tissue and further segmented into “tumor” vs “stroma” areas according to CD45+ staining. Deconvolution of data was performed using SpatialDecon algorithm to estimate cell population within TLS. We then evaluated the association between immune cell composition and response to ICB in each segment. In a validation cohort, we performed multiplexed-IHF assay enabling detection of T cells (CD8/GzmA/CD4/FoxP3/CD56) and B cells. These panel was applied to whole sections baseline sarcoma samples. We investigated the association between immune cell composition and clinical benefit in term of progression-free survival (PFS) and overall survival (OS). Results: Six patients were selected for the exploratory cohort, including 3 R and 3 NR. Among the top immune cell infiltrate within TLS segment, NR demonstrated higher Treg infiltrate versus R in “no B-cells” compartment (3.4% vs 2.0%, respectively; p=0.010), whereas no association was observed between Treg infiltration and response to ICB in both stromal (p=0.67) or tumor cells (p=0.36) compartments from tumor area. In the validation cohort (N=16), we observed that Treg density within TLS was higher in NR versus R (p=0.0059). Patients with Treg-enriched TLS had shorter PFS (2.6 vs 11.1 months, p=0.042) and OS (9.0 vs 18.3 months, p=0.12) compared to those with Treg-low TLS infiltration. Concordantly, the CTLA-4 key Treg regulator gene was upregulated in the TLS regions from NR. Conclusions: Altogether, our findings suggest that the presence of Treg within TLS may exert a negative influence on the capacity of TLS to generate an effective antitumor immune response in sarcoma patients treated with ICB, providing new insights in understanding role of TLS in antitumor immunotherapy. Citation Format: Florent Peyraud, Jean-Philippe Guegan, Christophe Rey, Marina Pulido, Emmanuelle Bompas, Sophie Piperno-Neumann, Christine Chevreau, Nicolas Penel, François Bertucci, Maud Toulmonde, Carine Bellera, Catherine Sautès-Fridman, Antoine Bougoüin, Coralie Cantarel, Michèle Kind, Mariella Spalato-Ceruso, Bérengère Dadone-Montaudie, Jean-Yves Blay, Wolf Herman Fridman, François Le Loarer, Alban Bessede, Antoine Italiano. High regulatory T cells infiltrate within tertiary lymphoid structure restricts response to immune checkpoint blockers in sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2578.
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Kalic, Jovanka. « Beograd u XII veku - tvrdjava-grad-polis ». Zbornik radova Vizantoloskog instituta, no 40 (2003) : 91–96. http://dx.doi.org/10.2298/zrvi0340091k.
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(francuski) L'histoire de Belgrade au XIIe est document?e par diverses sources historiques qui, toutefois, relatent pour l'essentiel des ?v?nements li?s ? l'histoire de la ville ? cette ?poque. En ce sens, compte tenu de la position de la ville sur les rives de la Save et du Danube, c'est-?-dire pour l'?poque, sur la fronti?re nord de l'Empire byzantin face au royaume de Hongrie, les guerres opposant ces deux Etats constituent le th?me le plus fr?quemment des ?crivains m?di?vaux. S'agissant de la ville m?me les sources du XIIe si?cle ne nous en offrent aucune description pr?cise. Les auteurs grecs et latins se contentent le plus souvent de faire ?tat de quelques donn?es de base ? son sujet, ?voquant sa position g?ographiques et son aspect. L'auteur de ce travail communique une partie des r?sultats d'une analyse comparative des donn?es sur Belgrade au XIIe si?cle contenues dans les oeuvres des contemporains et t?moins visuels. Particuli?rement importantes sont ici les donn?es conserv?es dans l'oeuvre historique de Jean Kinnamos, qui a s?journ? ? Belgrade en 1165, puis les donn?es tir?es du texte du Pseudo-Ansbert sur la croisade de l'empereur allemand Fr?d?ric Ier Barberousse (1189), les donn?es des sources hongroises (Chronicon pictum Vindobonense), ainsi que les r?sultats des fouilles arch?ologiques effectu?es sur le site m?me de Belgrade. Jean Kinnamos d?signe toujours Belgrade comme une poliz et les sources latines comme une civitas. On rencontre aussi le terme arx d?signant une partie de l'agglom?ration ceinte de remparts. La ville fortifi?e de Belgrade s'est d?velopp?e au moyen ?ge sur l'aire de l'ancien camp militaire romain de Singidunum. Cet espace ?tait alors utilis? afin de r?pondre aux besoins militaires et administratifs de l'Empire byzantin. L'?poque des Comn?nes (1081-1185) voit ainsi la formation a Belgrade d'un important centre militaire et administratif sur une fronti?re menac?e. Le ch?teau de petites dimensions (136 *60 m) mis au jour lors de fouilles arch?ologiques syst?matiques dans la partie appel?e Ville Haute n'?tait qu'une partie de la ville fortifi?e. Avec le temps l'agglom?ration urbaine a d?bord? ? l'ext?rieur des remparts, mais lors des nombreuses guerres c'est elle qui a ?t? le plus expos?e aux destructions. Belgrade faisait partie des anciennes villes ?piscopales de l'?poque romaine et byzantine.
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Patricelli, Matthew P., Kristen A. Baltgalvis, Kelsey N. Lamb, Kent T. Symons, Chu-Chiao Wu, Melissa A. Hoffman, Aaron N. Snead et al. « Abstract IA003 : Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase ». Molecular Cancer Therapeutics 23, no 6_Supplement (10 juin 2024) : IA003. http://dx.doi.org/10.1158/1538-8514.synthleth24-ia003.
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Abstract The WRN helicase serves as a key target in the treatment of cancers characterized by microsatellite instability (MSI) because it plays a crucial role in resolving harmful non-canonical DNA structures that arise in cells with defective mismatch repair systems. Despite the critical functions of human DNA and RNA helicases, no drugs targeting these enzymes have been approved, largely due to the difficulties in identifying potent and selective inhibitors. In this study, we present the chemoproteomics-based identification of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This inhibitor specifically interacts with a cysteine residue (C727) within the helicase domain, which undergoes inter-domain movement during the DNA unwinding process. VVD-133214 reacts with the WRN protein in a nucleotide cooperative manner, promoting stable, compact structures that impede the enzyme's dynamic flexibility essential for its helicase activity. Inhibition of WRN by VVD-133214 leads to extensive double-stranded DNA breaks, nuclear enlargement, and ultimately cell death, specifically in MSI-high cells but not in microsatellite stable cells. The inhibitor demonstrated good tolerance in mice and significant tumor reduction in various MSI-high colorectal cancer cell lines and patient-derived xenograft models. Our findings highlight an allosteric strategy to inhibit WRN function that avoids interference from the endogenous ATP cofactor in cancer cells and positions VVD-133214 as a promising therapeutic candidate for patients with MSI-high cancers. Citation Format: Matthew P. Patricelli, Kristen A. Baltgalvis, Kelsey N. Lamb, Kent T. Symons, Chu-Chiao Wu, Melissa A. Hoffman, Aaron N. Snead, Xiaodan Song, Thomas Glaza, Shota Kikuchi, Jason C. Green, Donald C. Rogness, Betty Lam, Maria E. Rodriguez-Aguirre, David R. Woody, Christie L. Eissler, Socorro Rodilles, Seth M .Negron, Steffen M. Bernard, Eileen Tran, Jonathan Pollock, Ali Tabatabaei, Victor Contreras, Heather N Williams, Martha K. Pastuszka, John J. Sigler, Piergiorgio Pettazzoni, Markus G. Rudolph, Moritz Classen, Doris Brugger, Christopher Claiborne, Jean-Marc Plancher, Isabel Cuartas, Joan Seoane, Laurence E. Burgess, Robert T. Abraham, David S. Weinstein, Gabriel M. Simon, Todd M. Kinsella. Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA003.
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Blaess, J., J. Walther, J. E. Gottenberg, J. Sibilia, L. Arnaud et R. Felten. « AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS : A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE ». Annals of the Rheumatic Diseases 79, Suppl 1 (juin 2020) : 1464.1–1465. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1124.
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Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared
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GOCKO, x. « Exercer n° 200 : une référence pour tous ! » EXERCER 35, no 200 (1 février 2024) : 51–52. http://dx.doi.org/10.56746/exercer.2024.200.51.
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200 numéros d’exercer… Dans le numéro 80 de janvier 2008, premier numéro en ligne, l’éditorial signé par Pierre-Louis Druais, Patrick Chevalier et Denis Pouchain se terminait par : « Bonne lecture, mais critique s’il vous plaît. Toute l’équipe est à votre écoute pour que vive et grandisse exercer, la revue française de médecine générale. » La citation accolée à cette conclusion était « les étoiles naissent dans l’espace ». Dans ce numéro, la rédaction vous propose de découvrir d’autres citations, évoquées par ce numéro 200, celles de membres du comité de lecture et de relecteurs, qui entourent le premier éditorial de la revue. Pour ce numéro 200, l’éditorial vous propose 20 citations de films de tous les genres, et contrairement à l’habitude, aucune référence. Et comme « une citation sans référence est à peu près aussi utile qu’une horloge sans aiguilles »0, la mission pour les lecteurs est simple : trouver la référence ! Alors la revue exercer a-t-elle grandi ? Oui, simultanément à la filière universitaire de médecine générale, et ce n’est pas fini. Les utopistes de la rédaction veulent l’emmener « Vers l’infini et au-delà »1. Notre maître mot est « N’aie pas peur de rêver plus gros »2, en atteste la dernière plénière exercer au congrès de Lyon où « Je peux vous dire que Johnny Hallyday au stade de France, à côté c’est un Playmobil dans un évier »3. Comment faisons-nous pour rêver la suite ? Eh bien « La maison n’accepte pas l’échec »4 et nous savons que « les records sont faits pour être battus »5. Nous sommes conscients de notre mission : fournir aux soignants de soins de santé primaires des données indépendantes et EBM pour, in fine, améliorer l’état de santé des usagers : « à grand pouvoir, grandes responsabilités »6. Comment faisons-nous pour assurer cette mission ? « Force de frappe, esprit d’équipe »7. Cet esprit d’équipe insufflé par Jean-Pierre Lebeau « O captain, my captain »8 a été rapidement perçu par la dernière arrivée, Karolina Griffiths, autrice de podcasts, et elle peut déjà témoigner qu’« on ne laisse pas Bébé dans un coin »9. De quelle suite rêvons-nous ? Vous en avez peut-être entendu parler et « Quand une rumeur ne meurt pas, c’est que ce n’est pas une rumeur »10, nous travaillons à l’indexation dans Medline pour 2024, après Clarivate Analytics (ex-Web of Science) en 2018. Parallèlement, nous allons aussi travailler à un archivage HAL science ouverte : « HAL, ouvre la porte, s’il te plaît »11. Vous doutez ? « Votre manque de foi me consterne »12, ayez confiance, « l’union fait la force ! La foi fait l’union ! »13, notre équipe sait que « Seule compte la volonté, la volonté d’agir »14 et « rien n’est plus fort que le coeur d’un volontaire »15. Souvent l’éditorial présente le contenu du numéro, et à ce stade de la lecture vous vous demandez quel est ce contenu ? D’autant plus qu’exercer « C’est comme une boîte de chocolats, on ne sait jamais sur quoi on va tomber »16. Ce numéro contient des réponses à des questions issues de notre pratique, et il contient aussi des réponses à des questions que nous ne nous étions pas encore posées…Superflu, vous pensez ? « Rien n’est plus nécessaire que le superflu »17. Avec ce numéro 200, vous savez désormais que l’étoile exercer est née dans l’espace, et cet espace « C’est votre espace. Vous le possédez »18. Une étoile, mais pas une star, conservons notre humilité, car nous savons que « l’arrogance et l’introspection font rarement bon ménage »19. Soyons optimistes et forces de proposition, car « Peu importe ce qu’on pourra vous dire, les mots et les idées peuvent changer le monde »20.
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KAHN, G. « Review. Dictionaire critique de la langue francaise. Tome I : A-D. Tome 2 : E-N. Tome 3 : O-Z. Reproduction facsimile. Preface par Philippe Caron et T. R. Wooldridge. Feraud, Jean-Francois ». French Studies 52, no 4 (1 octobre 1998) : 469. http://dx.doi.org/10.1093/fs/52.4.469-a.
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Cardin, L., A. Poupet et J. P. Onesto. « First Report of Cucumber mosaic virus in Teucrium fruticans ». Plant Disease 87, no 2 (février 2003) : 200. http://dx.doi.org/10.1094/pdis.2003.87.2.200c.
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Teucrium fruticans (shrubby germander), family Lamiaceae, is a hardy shrub. Being drought tolerant, it is widespread in the Mediterranean area. Because it is readily propagated through cuttings, it is also planted in hedges. In 1997 and 2000, respectively, yellow chlorotic areas were observed on the foliage of T. fruticans in Saint Jean Cap Ferrat (France) and San Remo (Italy). These symptoms were distinct from those produced by a rust that frequently affects T. fruticans in these areas. Viruses from both locations were identified as Cucumber mosaic virus (CMV) based on the following: (i) symptoms after mechanical inoculation of Nicotiana tabacum cv. Xanthi nc, N. tabacum cv. Samsum, Chenopodium quinoa, C. amaranticolor, Vigna unguiculata cv. Black, and Cucumis sativus cv. Poinsett; (ii) the morphology of particles observed in electron microscopy of uranyl acetate stained leaf dips from tobacco; and (iii) positive result from leaves of diseased T. fruticans and mechanically inoculated host plants cited above based on enzyme-linked immunosorbent assay (ELISA) using CMV antisera. On tobacco cv. Xanthi nc, the French (F) and Italian (I) isolates first induced essentially necrotic rings on the inoculated leaves followed by the same systemic symptoms as described above. The two isolates were cloned from local lesions after two successive inoculations in V. unguiculata cv. Black, multiplied in tobacco, purified with the citrate-chloroform method, and stabilized with formaldehyde (1). The serotype determination was made by double immunodiffusion in agar gel with the CMV-D and CMV-To strains and homologous antisera (1,2). The formation of spurs and antigen-antibody lines indicated that both isolates belonged to the ToRS serotype (1). Thirty plants of T. fruticans cv. Azureum, first tested negative for CMV using ELISA, were mechanically inoculated with the F isolate (25 plants) and the CMV-D strain (five plants) and cultivated in a hydroponic system. Three months later, plants inoculated with the F isolate were positive for CMV using ELISA and displayed clear symptoms with chlorotic spots, which were sometimes ring-shaped. As plants mature, symptoms tend to disappear on young shoots. For the CMV-D strain, three plants of five were ELISA positive, but did not show any typical symptoms. This report demonstrates the infection of T. fruticans by CMV and the symptom induction by some CMV isolates. In September 2002, two CMV isolates were collected from T. fruticans in public gardens in Menton (France) and Genoa (Italy). These new isolates have the same characteristics as those described in this report. References: (1) J. C. Devergne and L. Cardin. Ann. Phytopathol. 7:225, 1975. (2) M. H. V. van Regenmortel. Adv. Virus Res. 12:207, 1966.
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BARBOSA, CLEIDIMAR SILVA, Mariluce Paes de Souza et JEAN MARCOS DA SILVA. « APLICAÇÃO DE TECNOLOGIAS PARA PRODUÇÃO EM CADEIAS PRODUTIVAS DE RECURSOS AMAZÔNICOS ». Revista de Administração e Negócios da Amazônia 13, no 4 (30 décembre 2022) : 1–11. http://dx.doi.org/10.18361/2176-8366/rara.v13n4p1-11.
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O contexto amazônico tem como marca sua biodiversidade e a diversidade sociocultural com significativo potencial produtivo local de recursos mobilizáveis e mobilizadores. O presente trabalho busca integrar os estudos em cadeia produtivos de recursos Amazônicos com as áreas de tecnologias prioritárias por organizações cooperativas na Região Central no estado de Rondônia. Os dados serão coletados utilizando roteiros de entrevistas semi-estruturados. Inicialmente o estudo foi desenvolvido através de revisão bibliográfica, buscando entender os conceitos de cadeia produtiva e as abordagens sobre tecnologia de produção de produtos extrativistas. Neste artigo apresenta-se esta revisão bibliográfica utilizada. Dentro dos resultados o presente trabalho buscou abordar discussões teóricas acerca da temática: produtos florestais não madeiráveis, cadeias produtivas e tecnologia e informação. Para Pedrozo et al. (2011), os Produtos florestais não madeiráveis – PFNMs são recursos provenientes de florestas nativas, sistemas agroflorestais e plantações incluindo também plantas medicinais e de uso alimentício, frutas, castanhas, resinas, látex, óleos essenciais, fibras, forragem, fungos, fauna e madeira para a fabricação de artesanato, sendo a floresta amazônica a maior fonte de fornecimento desses produtos. No âmbito das cadeias produtivas, segundo Labone (1987) esta é definida como uma sequência de atividades físicas desempenhadas para a produção de um bem. Além disso, podemos associar este termo ao vocábulo agroflorestais, nas quais há uma abertura para discutir a extração de Produtos Florestais Não Madeiráveis (PFNMs). Por fim tecnologia é amplamente utilizada em diferentes áreas da humanidade. Para Klinge (2000), a mentalidade tecnologista é uma forma de se aproximar da realidade que surgiu na modernidade. Os resultados obtidos por coleta de dados não se fez possível por razões do cenário pandemico. O presente trabalho buscou abordar no âmbito teórico, pois por razões da pademia não se pode contemplar os questionários e análises qualitativas, o que fica como possibilidade futura para trabalho complementar. Refências ARAÚJO, J. P. F. de, et al. Evidenciação das demonstrações contábeis das entidades portadoras do título de utilidade pública federal de Rondônia. Revista Eletrônica de Administração e Turismo , [s.l.], v. 6, n. 3, p. 538-556, 2015. CHAMBERLAIN, J.L., BUSH, R. & HAMMETT, A.L. Non-Timber Forest Products: The other forest products. Forest Products Journal, v. 48, 1998. KLINGE, Germán Doig. Tecnologia, Utopia e Cultura. [s.d.]. 13 p. 2000. Disponível em:<http://www.fides.org.br/artigo08.pdf>. Acesso em: 04 Mar. 2021. LABONNE, M. Sur Le Concept De filière économie agro-alimentaire. Anais. Séminaire interdisciplinaire sur les politiques alimentaires, Paris, p. 137-149, 1987. Disponível em: http://www.documentation.ird.fr/hor/fdi:24865 Acesso em: 11 jan. 2021. MACIEL, R. C. G.; DE OLIVEIRA, O. F.; DA SILVA, J. M. Production and destination of solid waste in the Chico Mendes Extrative Reserve, Acre, Brazil. Journal of Environmental Protection, 10, 791-806, 2019. https://doi.org/10.4236/jep.2019.106047. NARDELE, Marcelle; CONDE, Igor. Sistemas agroflorestais, 2012. Diponível em: http://r1.ufrrj.br/cfar/d/download/Apostila%20Agroflorestas.pdf Acesso em: 22 Fevereiro 2021. OLIVEIRA, O. F.; MACIEL, R. C. G.; SILVA, J. M.; CAVALCANTE FILHO, P. G. Programa Território da Cidadania: Políticas públicas para o desenvolvimento rural em Rondônia. Revista Brasileira de Gestão e Desenvolvimento Regional, v. 14, n. 2, p. 347-370, 2018. DOI: https://doi.org/10.54399/rbgdr.v14i2.3597 PEDROSO, E.A et al. Produtos Florestais Não Madeiráveis (PFNMS): as Filières do Açaí e da Castanha da Amazônia. Revista de Administração e Negócios da Amazônia - RARA. v. 3, n. 2, p 88-112, 2011. RODRIGUES, C.; et al. "Gestão e responsabilidade socioambiental: estudo multicaso no setor hoteleiro da cidade portal da Amazônia". Revista Estudo & Debate, v. 24, n. 1, 42-66, 2017. SILVA, J. M.; Paes-de-Souza, M.; Souza Filho, T. A.; Passos-da-Silva, R. Custos e Preços da Castanha-da-amazônia nos estados do Acre e Rondônia. In. Custos e Agronegócio On Line, v. 13, n. 2, 2017. SILVA, J. M.; Paes-de-Souza, M.; Souza Filho, T. A.; Cadeia produtiva da Castanha-da-Amazônia nos Estados do Acre e Rondônia. In. Brazilian Journal of Development, v. 6, n. 11, 2020. Silva, Jean, et al. "PROCESSO PRODUTIVO DO PFNM PINHÃO DAS ARAUCÁRIAS: O CASO DO EXTRATIVISTA_JDZ NO RIO GRANDE DO SUL." Revista de Administração e Negócios da Amazônia, v. 12, n. 1, 2020. SILVA, Jean Marcos da, et al. "POLÍTICAS PÚBLICAS DE GARANTIA DE PREÇOS MÍNIMOS PARA PRODUTOS DA SOCIOBIODIVERSIDADE (PGPMBio): COMPOSIÇÃO DO CUSTO DE EXTRAÇÃO DE CASTANHA DA AMAZÔNIA EM RONDÔNIA E ACRE." Revista de Administração da UFSM 15.1 (2022): 62-82. SOUZA, Ivonete F. de. Cadeia produtiva de castanha-do-Brasil (Bertholletia excelsa) no Estado de Mato Grosso. Campo Grande: Departamento de Economia e Administração, Universidade Federal de Mato Grosso do Sul, 2006, 141 p. Dissertação de Mestrado. VIEIRA PINTO, Álvaro. O conceito de Tecnologia. Rio de Janeiro: Contraponto, 2005.
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Pavy-Guilbert, Élise, et Hélène Cussac. « Jacques-Henri Bernardin de Saint-Pierre , Œuvres complètes , t. III : Œuvres scientifiques : Études de la nature et textes périphériques , éd. Colas Duflo, collab. Joël Castonguay-Bélanger et Jean-Michel Racault , dir. Jean-Michel Racault , Paris, Classiques Garnier, coll. « Bibliothèque du 18 e siècle », n° 42, 2019, 1134 p. » Dix-huitième siècle 52, no 1 (1 octobre 2020) : III. http://dx.doi.org/10.3917/dhs.052.0493a03.
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Diéras, Véronique, Elise Deluche, Amélie Lusque, Barbara Pistilli, Thomas Bachelot, Jean-Yves Pierga, Frédéric Viret et al. « Abstract PD8-02 : Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status : A phase II study with biomarkers analysis (DAISY) ». Cancer Research 82, no 4_Supplement (15 février 2022) : PD8–02—PD8–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd8-02.
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Abstract Background: The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) demonstrated efficacy in heavily pretreated HER2-over- and HER2-low expressing ABC (1, 2). We aimed to assess the activity of T-DXd in HER2-over-, HER2-low and HER2-nul expressing ABC, to describe the drug mechanisms of action in the 3 cohorts and to identify biomarkers associated to drug response or resistance. Study Description: DAISY is a multicenter, open-label phase II trial designed to assess the efficacy of single agent T-DXd at 5.4 mg/kg dose in ABC with extensive biomarkers analysis. Three cohorts of patients were included: Cohort 1 (HER2 over-expressing: HER2 3+ on immunohistochemistry (IHC) or HER2 IHC2+/in situ hybridization [ISH]+), Cohort 2 (HER2 low-expressing: IHC1+ or IHC2+/ISH-) and cohort 3 (HER2-nul: IHC0+). Biopsy of metastatic sites was performed: at baseline, on treatment (mandatory for cohort 1, optional for cohort 2/3) and at tumor progression; blood samples for ctDNA were collected at baseline. The primary endpoint was the Best Overall Response (BOR) in each cohort, according to the investigator assessment. Secondary endpoints were BOR by central assessment, clinical benefit rate, duration of response (DOR), progression-free (PFS), overall survival (OS) and safety. Results:185 women and 1 man were enrolled between November 2019 and March 2021. Among the patients enrolled in the safety population (see Table 1), median (range) age was 55 (24-82) years, all received at least one prior line of therapy and 12 patients were TN. Table 2 shows investigator-reported T-Dxd activity in the 3 cohorts at a median follow-up of 10.1 months [95%CI: 9.2-11.1]. A total of 170 patients (95%) had at least one treatment-related toxicity. Key grade ≥3 treatment-related toxicities included neutropenia (10.6% of patients), fatigue (5.6%), leucopenia (4.5%), vomiting (4.5%) and anemia (3.4%). A total of 4 patients had drug-related interstitial lung disease or pneumonitis (grade 1 in 3 patients and grade 2 in 1 patient), 11 patients discontinued treatment due to treatment-related adverse events. No drug-related deaths occurred. Conclusions: T-DXd showed clinically meaningful activity in patients with HER2-overexpressing ABC and interestingly also in those with HER2low and HER2-nul ABC. Safety profile was consistent with previous reports. 1.Modi S et al N Engl J Med 2020 2.Mosi S et al J Clin Oncol 2020 Table 1.Analysis populationsTotalCohort 1 (HER2 over-expressing)Cohort 2 (HER2 low-expressing)Cohort 3 (HER2 non-detected)Enrolled population186727440Safety population*179687338 (including 12 TN)Full analysis Set**176687236TN: Triple Negative. *: safety population = enrolled population except 7 patients who did not receive at least one dose of study drug. **: Full Analysis Set = safety population except 3 patients (2 who did not have a valid first post-baseline assessment of disease status or who did not have progressive disease and 1 who did not have at least one radiologically measurable lesion according to RECIST v1.1) Table 2.T-DXd activity in the three cohorts according to investigator assessmentTotalCohort 1Cohort 2Cohort 3BOR confirmedn/N82/176 (46.6%)47/68 (69.1%)24/72 (33.3%)11/36 (30.6%)[95%CI][39.1; 54.2][56.7; 79.8][22.7; 45.4]16.3; 48.1]Median DORmonths7.69.97.66.8[95%CI][6.2; 9.7][5.4; NR][4.4; 8.7][2.8; 8.3]Median PFSmonths6.911.16.74.2[95%CI][6.7; 8.7][8.4; NR][4.6; 8.5][2.1; 6.9]NR: Not Reached Citation Format: Véronique Diéras, Elise Deluche, Amélie Lusque, Barbara Pistilli, Thomas Bachelot, Jean-Yves Pierga, Frédéric Viret, Christelle Levy, Laura Salabert, Fanny Le Du, Florence Dalenc, Christelle Jouannaud, Laurence Venat-Bouvet, Jean-Philippe Jacquin, Xavier Durando, Thierry Petit, Céline Mahier - Aït Oukhatar, Thomas Filleron, Maria Fernanda Mosele, Magali Lacroix-Triki, Agnès Ducoulombier, Fabrice André. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: A phase II study with biomarkers analysis (DAISY) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-02.
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Dusengimana, Jean-Marie Vianney, Jean de Dieu Uwihaye, Amanda Fata, David Tuyisenge, Aphrodis Ndayisaba, Vestine Rugema, Marie Louise Uwineza, Lawrence N. Shulman, Cyprien Shyirambere et Lydia E. Pace. « Abstract 1 : A Learning Collaborative Model to Empower Rural Rwandan Health Centers to Improve the Quality of Screening for Women’s Cancers ». Cancer Epidemiology, Biomarkers & ; Prevention 32, no 6_Supplement (1 juin 2023) : 1. http://dx.doi.org/10.1158/1538-7755.asgcr23-abstract-1.
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Abstract Purpose: Screening and early detection initiatives for breast and cervical cancer are public health priorities in sub-Saharan Africa, but sustainable strategies to monitor screening quality in rural health facilities are not well-described. We sought to empower rural primary care clinicians to monitor and improve screening quality and integrate quality improvement (QI) into routine practice through a learning collaborative in 8 health facilities participating in a breast and cervical cancer screening initiative in Burera district, Rwanda. We evaluated the model’s impact on participant knowledge/attitudes and QI projects’ success. Methods: Two-day didactic sessions in March 2022 addressed quality measurement and QI implementation. QI knowledge/attitudes were assessed before and after training using a brief written survey and compared using paired t-tests. Participants (all nurses) then identified a cancer screening problem at their health facility that could be solved using QI methods and planned projects. All health center (HC) trainees focused on increasing the proportion of eligible women screened for cervical cancer in their sectors, via educational campaigns. District hospital (DH) team members aimed to reduce missed referral visits. At subsequent meetings, teams discussed projects and next steps. Results: Three clinicians from each of 7 HCs and 2 from the DH (n=23) participated in training; 22 took pre- and post-training surveys. Baseline mean knowledge scores (66.5%,SD 11.8) improved following training (82.4%,SD 12.0,p<0.001). After training, 22(100%) reported interest in being more engaged in QI. In the 6 months following project implementation, HCs saw a 4.8-fold increase in the mean number of patients screened across 7 HCs (35.4,SD 17.1) compared to 6 months prior (7.5,SD 2.6). Efforts to reduce missed visits could not be assessed due to inability of the cancer screening electronic medical record to track patients across facilities. Conclusion: A learning collaborative model engaged rural primary care clinicians in evaluating and improving cancer screening practices. QI knowledge improved and HCs met initial project goals. Though projects focused on patient volume, future initiatives should examine other critical quality measures i.e., referral completion and time to cancer diagnosis. Improving data collection systems is essential to facilitate availability of follow-up data and patient tracking and empower clinicians to monitor care quality. Citation Format: Jean-Marie Vianney Dusengimana, Jean de Dieu Uwihaye, Amanda Fata, David Tuyisenge, Aphrodis Ndayisaba, Vestine Rugema, Marie Louise Uwineza, Lawrence N. Shulman, Cyprien Shyirambere, Lydia E. Pace. A Learning Collaborative Model to Empower Rural Rwandan Health Centers to Improve the Quality of Screening for Women’s Cancers [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 1.
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Rappaport, Amy R., Christine D. Palmer, Annie Shen, Claudia X. Dominguez, Meghan G. Hart, Lauren D. Kraemer, Sonia Koulavouth et al. « Abstract 3578 : Optimization of shared neoantigen vaccine design to increase vaccine potency : From bench to bedside and back ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 3578. http://dx.doi.org/10.1158/1538-7445.am2022-3578.
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Abstract Vaccines targeting neoantigens identified from common tumor driver mutations are of increasing interest as evidence of clinical benefit builds, and opportunities to combine such vaccines with immune modulators are growing. Our individualized neoantigen vaccine (GRANITE) has shown clinical benefit and strong, consistent CD8 T cell induction in patients. We have developed an analogous off-the-shelf product (SLATE) targeting shared neoantigens that offers manufacturing simplicity and faster administration to patients with shared driver mutations. A Phase 1/2 trial of a heterologous prime/boost vaccine regimen using a chimpanzee adenovirus (ChAd) prime and self amplifying mRNA (SAM) boosts (SLATE, NCT03953235) was initiated to assess safety, tolerability, and immunogenicity in patients with advanced cancers. SLATE version 1 encodes 20 unique neoantigens to various shared driver mutations (KRAS, TP53, etc.). Patients were selected if their tumors harbored one of the 20 neoantigens encoded by the vaccine cassette and an HLA Class I allele that presents that neoantigen. Administration of ChAd prime and repeated administration of 30, 100, or 300µg SAM doses were safe and well tolerated in all subjects dosed (n=26), with no evidence of increasing reactogenicity with sequential dosing. Early efficacy signals (molecular responses; one unconfirmed RECIST response) were observed in NSCLC subjects all treated with and progressed on prior anti-PD(L)1. Analysis of T cell responses pre and post immunizations by ex vivo IFNγ ELISpot did not show robust responses to KRAS neoantigens across all patients. However, objective CD8 T cell responses to KRAS antigens post vaccination were detectable after in vitro stimulation, suggesting the induction of low-level KRAS specific T cell responses in vivo. In contrast, HLA-matched responses to TP53 neoantigens encoded by the vaccine were consistently detected via ex vivo ELISpot in these same patients. These data suggests that an immunodominant T cell response to the TP53 mutations may have outcompeted the response to the less immunogenic KRAS mutations restricted and presented by the same HLA in vivo. Differential surface peptide-HLA (pHLA) density may explain these discordant findings, and subsequent targeted mass spectrometry analyses revealed detection of TP53 pHLA complexes at a higher frequency compared to KRAS mutations in single HLA-allele cell lines. Redesigned vaccine cassettes excluding the TP53 epitopes and repeating KRAS epitopes demonstrated increased immune responses (ex vivo IFNγ ELISpot) compared to cassette version 1 in HLA transgenic mice, further supporting the tumor neoantigen immunodominance hierarchy observed in humans dosed with SLATE version 1. A re-designed product (SLATE v2) focusing exclusively on KRAS mutations (G12C, G12D, G12V and Q61H) is currently being assessed in phase 2 in patients with advanced KRAS-driven tumors. Citation Format: Amy R. Rappaport, Christine D. Palmer, Annie Shen, Claudia X. Dominguez, Meghan G. Hart, Lauren D. Kraemer, Sonia Koulavouth, Martina Marrali, Jason R. Jaroslavsky, Charmaine N. Nganje, Ciaran D. Scallan, Sue-Jean Hong, Leonid Gitlin, Monica Lane, Daniel V. Catenacci, Chrisann Kyi, David P. Carbone, Hossein Borghaei, Raphael Rousseau, Andrew Ferguson, Karin Jooss. Optimization of shared neoantigen vaccine design to increase vaccine potency: From bench to bedside and back [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3578.
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Tcyganov, Evgenii N., Taekyoung Kwak, Xue Yang, Adi N. Poli, Colin Hart, Avishek Bhuniya, Joel Cassel et al. « Abstract 5274 : Targeting retinoblastoma protein in tumor-associated macrophages suppresses ovarian cancer progression ». Cancer Research 84, no 6_Supplement (22 mars 2024) : 5274. http://dx.doi.org/10.1158/1538-7445.am2024-5274.
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Abstract Ovarian cancer is characterized by an immunosuppressive tumor microenvironment (TME) maintained by tumor-associated M2-like macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. An effective approach to target TAMs in ovarian cancer treatment is currently not available, but would be expected to release immunosuppressive pressure, enable a robust T cell response and improve immunotherapy outcomes. Retinoblastoma protein (Rb) is a well-known tumor suppressor and regulator of tumor cell proliferation. Accumulating evidence demonstrates its role in immune cells, in myeloid cells, in particular. However, these mechanisms remain poorly understood. Based on our previous data on Rb role in myeloid cell viability, we decided to test the effects of Rb modulation in macrophages. We used the small molecule, AP-3-84 compound, and newly developed analogs which bind the LxCxE motif of Rb and disrupt Rb interaction with its binding adaptor proteins. AP-3-84 induced cell death preferentially in macrophages, but not in T cells or tumor cells (without effects on cell proliferation). Gene and protein expression analysis revealed that Rb targeting induced major intracellular stress response programs and p53/mitochondria-related cell death pathways in TAMs. Moreover, we found that M2 type polarized macrophages expressed higher levels of Rb compared to M1 macrophages. In agreement with that, M2 type macrophages were significantly more sensitive to AP-3-84 treatment than M1 polarized cells. Next, we demonstrated that low dose therapeutic use of AP-3-84 in mice bearing ovarian cancer significantly re-shaped the immune composition of the TME by depleting TAMs and inducing remarkable T cell infiltration. Importantly, these AP-3-84 effects were immune-mediated, since identical AP-3-84 treatment in NSG immunodeficient mice had no effect on tumor growth. Similarly, anti-CD4/CD8 depletion also reverted AP-3-84 effects on cancer inhibition. An analysis of activation and differentiation markers in myeloid and T cell subsets in the TME showed a shift of the remaining macrophages towards an M1-like cell type accompanied by activation of T cells. Using ovalbumin-overexpressing ovarian cancer cell line, we documented the accumulation of antigen-specific T cells in the TME associated with a substantial delay of ovarian cancer upon AP-3-84 therapeutic Rb targeting. Ex vivo, we observed an analogous cell death induction by AP-3-84 treatment in TAMs from post-surgery ascites from ovarian cancer patients. Using available datasets, we further documented that an increase in Rb expression in the TME myeloid cells is associated with poorer prognosis. Overall, our data supports that therapeutic targeting of the Rb LxCxE motif is a promising approach for ovarian cancer treatment due to depletion of TAMs and re-shaping the ovarian cancer TME. Citation Format: Evgenii N. Tcyganov, Taekyoung Kwak, Xue Yang, Adi N. Poli, Colin Hart, Avishek Bhuniya, Joel Cassel, Andrew Kossenkov, Noam Auslander, Paridhima Sharma, Mark G. Cadungog, Stephanie Jean, Sudeshna Chatterjee-Paer, David Weiner, Laxminarasimha Donthireddy, Bryan Bristow, Rugang Zhang, Joseph M. Salvino, Luis J. Montaner. Targeting retinoblastoma protein in tumor-associated macrophages suppresses ovarian cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5274.
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Carralot, Jean-Philippe, Kea Martin, Rubén Alvarez Sanchez, Roy Meoded, Caoimhe Herr, Philipp Moosman, Arnaud Goepfert, Andrew Chi, Vijaya J. Pattabiraman et Bertolt Kreft. « Abstract 1850 : A first-in-class PD1-IL18 immunocytokine (BPT567) targets PD-1+ IL18R+ CD8+ T effector cells enriched in the tumor microenvironment and exhibits potent antitumor efficacy with excellent tolerability ». Cancer Research 83, no 7_Supplement (4 avril 2023) : 1850. http://dx.doi.org/10.1158/1538-7445.am2023-1850.
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Abstract Immunocytokines (IC) leverage orthogonal mechanisms of action in one molecule to induce potent antitumor immune responses. PD-1-targeting ICs are of particular interest since they harbor the multifunctional ability to selectively target antigen-experienced PD-1+ CD8+ T cells enriched in the tumor microenvironment (TME), release them from PD-(L)1 pathway inhibition, be retained within the TME, and simultaneously deliver potent cytokine receptor stimulation to the same T cell in cis (cis-signaling). Interleukin (IL-18) is a proinflammatory cytokine that stimulates both innate and adaptive immunity and generates potent antitumor activity mediated by both T effector and NK cells. Recent evidence indicates that a subset of tumor-infiltrated PD-1+ CD8+ T effector cells hallmarked by high expression of IL-18 receptor exhibits a superior cytotoxic and proliferative phenotype. Hence, we developed a PD1-IL18 IC to specifically target and activate intratumoral IL-18R-expressing PD-1+ CD8+ T cells. We engineered a conjugatable variant of human IL-18 with enhanced potency and significant resistance to IL-18 binding protein (IL-18BP) and utilized this enhanced IL-18 payload to create a PD1-IL18 IC (BPT567) via site-specific chemical conjugation to a defined lysine residue within the heavy chain of an anti-human PD-1 antibody (Ab). Conjugation did not affect the basic properties of the Ab as neither binding to PD-1 nor the interaction with the neonatal Fc receptor (FcRn) or Fcγ receptors were significantly impacted. Of note, the conjugation handle in our enhanced IL-18 variant was inserted at a site distinct from its N- or C-terminus to preserve the full potency and selectivity of the IL-18 payload. As a result, BPT567 exhibits increased potency and marked resistance to IL-18BP inhibition compared to wild-type IL-18. In vivo, BPT567 shows striking antitumor efficacy in multiple syngeneic mouse tumor models that is superior to responses induced by an anti-PD-1 Ab alone, a non-targeted IL-18 IC or the combination of both agents. Our evidence suggests that the strong in vivo efficacy observed is attributed to a preferential activation of PD-1+ tumor-infiltrated immune cells. The excellent tolerability and large therapeutic window observed in mice may be driven by less potent immune cell activation in the periphery. Citation Format: Jean-Philippe Carralot, Kea Martin, Rubén Alvarez Sanchez, Roy Meoded, Caoimhe Herr, Philipp Moosman, Arnaud Goepfert, Andrew Chi, Vijaya J. Pattabiraman, Bertolt Kreft. A first-in-class PD1-IL18 immunocytokine (BPT567) targets PD-1+ IL18R+ CD8+ T effector cells enriched in the tumor microenvironment and exhibits potent antitumor efficacy with excellent tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1850.
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Curraj, E., F. Carlier, M. Dumonceaux, P. Evrard, B. Rondelet, J. P. Devogelaer et Y. Boutsen. « POS0495 PREVALENCE AND RISK FACTORS OF OSTEOPOROSIS IN A BELGIAN COHORT OF LUNG TRANSPLANTATION CANDIDATES : THE PROGRES STUDY ». Annals of the Rheumatic Diseases 82, Suppl 1 (30 mai 2023) : 509.2–510. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1799.
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BackgroundFew data are available on the incidence of osteoporosis (OP) in end-stage pulmonary diseases, particularly in lung transplant candidates. Yet, organ transplantation can be accompanied by low bone mineral density (BMD) owing to immunosuppressive therapy, particularly with oral glucocorticoids (GCs) use.ObjectivesOur primary aim was to evaluate the prevalence and therapeutic management of OP in lung transplant candidates. Our second objective was to determine the risk factors associated with OP, including the type of respiratory disorder.MethodsWe included 198 patients (103 women) out of 388 screened for lung transplantation at our institution between January 1998 and December 2020. BMD, measured by Dual-energy X-ray absorptiometry (DXA, Hologic (t-m)) at the lumbar spine (LS), total hip (TH), and femoral neck (FN), vertebral fracture assessment (VFA), as well as previous major osteoporotic fracture (MOF), were recorded. We systematically collected well-recognized OP risk factors, along with other factors suspected of affecting BMD such as inhaled (i) GCs use, pulmonary function tests, hypoxemia and type of pulmonary disorder.ResultsOP, as defined by BMD values (T-score ≤ -2.5) and/or fragility fracture (FF), MOF and/or vertebral fractures (VF), was observed in 118 patients (59.6%). Among these patients, 54 (45.8%) had only a T-score ≤ -2.5, while 36 (30.5%) had only an FF, with predominant vertebral fractures (77.8%). The median age (IQR) of the study population was 58 years (53.0-62.0), and 59 years in OP patients (54.2-62.0). Mean T-scores (±SD) were -1.62±1.52 at the LS, -1.43±1.05 at the TH and -1.98±1.14 at the FN. Mean T-scores (±SD) in OP patients were -2.15±1.31, -1.87±0.93 and -2.44±1.03, respectively. The mean (±SD) ten-year probability of major osteoporotic fracture assessed by the FRAX algorithms (FRAX score) was 11.6±11.2 %, and the mean FRAX adjusted to GCs dose (±SD) was 12.0±12.1 %. Nighty-eight patients (49.5%) achieved intervention threshold adjusted for age based on FRAX results and 110 patients (55.6%) when FRAX was adjusted to GCs dose. Seventy-eight OP patients (66.1%) achieved the FRAX intervention threshold, of whom 53 (67.9%) received calcium and/or vitamin D and 33 (42.3%) had received an add-on therapy, mostly a bisphosphonate (n=23, 69.7%) or denosumab (n=4, 12.1%). Eighty-four OP patients (71.2%) achieved the FRAX intervention threshold adjusted to GCs dose, of whom 59 (70.2%) received calcium and/or vitamin D and 37 (44.5%) had received an add-on therapy, mostly a bisphosphonate (n=25, 67.6%) or denosumab (n=5, 13.5%). Thirty-six OP patients (30.5%), 18 patients (33.3%) with only a T-score ≤ -2.5 and 12 patients with only an FF, did not receive any medication. In total, 153 patients had a chronic obstructive pulmonary disease (COPD, 77.3%), 33 an interstitial lung disease (ILD, 16.3%) and 12 (6.1%) suffered from another pulmonary disease. Among OP patients, 102 had a COPD (86.4%), 12 an ILD (10.2%) and 4 (3.4%) suffered from another pulmonary disease.Lower BMI, iGCs use, COPD, reduced FVC and severely impaired FEV1/FVC ratio were associated with OP. GCs treatment was associated with FF, regardless of the daily dosage.ConclusionMost of lung transplant candidates were suffering from OP and one third suffered from FF. Thus, performing DXA and VFA should be recommended in lung transplant candidates in order to start adequate osteoporosis treatment before lung transplantation. This is even more important in COPD patients, as this population displays an increased risk of OP compared to other end-stage diseases. OP diagnosis is important in those patients as their risk of fracture is likely to increase after transplantation. The large proportion of untreated (or insufficiently treated) patients stressed the need to develop specific strategies in this field. Finally, controlling some risk factors is crucial for the management and prevention of OP, for instance by, at least, tapering the dosage of both oral and inhaled GCs.Table 1.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsEdwin Curraj: None declared, François Carlier: None declared, Michel Dumonceaux: None declared, Patrick Evrard: None declared, Benoit Rondelet: None declared, Jean-Pierre Devogelaer: None declared, Yves Boutsen Speakers bureau: UCB, Grant/research support from: Viatris, Galapagos, Biogen, Amgen.
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Choquette, D., L. Bessette, L. Choquette Sauvageau, J. Brown, I. Ferdinand, P. Haraoui, M. Joly-Chevrier et al. « POS0057 WHICH ADVANCED TREATMENT SHOULD BE USED FOLLOWING THE FAILURE OF A FIRST-LINE ANTI-TNF IN PATIENTS WITH RHEUMATOID ARTHRITIS ? 15 YEARS OF EVIDENCE FROM THE QUEBEC REGISTRY RHUMADATA™ ». Annals of the Rheumatic Diseases 82, Suppl 1 (30 mai 2023) : 239.1–239. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1423.
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BackgroundSince 2000, advanced therapies (AT) have revolutionized rheumatoid arthritis (RA) treatment. Initially, TNF-targeted therapies were the only options. Then, therapies with different modes of action (OMA) appeared. Habits and medication availability often determine second-line AT choices. Research suggests that specific sequences provide better long-term effectiveness [1,2].ObjectivesEvaluate which alternative medication provides the best sustainability following first-line TNF failure.MethodsData from AT prescribed since January 2007 was extracted from RHUMADATA™. Patients were followed until treatment discontinuation, loss to follow-up, or November 25, 2022. A descriptive statistic was used to compare patient characteristics. Kaplan-Meier was used to compare treatment discontinuation rates.ResultsA total of 611 patients (320 TNFi and 291 1237 OMA were included. The mean age at diagnosis was 44.5 (14.4) and 43.9 (14.8) in the TNFi and OMA groups, and disease duration at treatment initiation (TI) was 14.1 (11.1) and 12.9 (12.9). Women made up 72.8% and 81.1% of these groups. The age-adjusted Charlson Comorbidity index (ACCI) was 2.15 (1.7) and 2.1 (1.7). Patients reported more comorbidities, pain and fatigue, longer duration of morning stiffness, and higher HAQ score and disease activity in the OMA group (Table 1). The physician’s global assessment of disease activity and the number of swollen and tender joints were also higher in the OMA group. OMAs retention was higher (Figure 1, logrank=0.0134) than TNFi retention following initial TNFi-IR. In a stratified analysis, rituximab (adjusted (Sidak) logrank=0.0048) had higher retention.ConclusionWhen a first TNFi fails, switching to an OMA, especially rituximab, appears to be the best strategy. Adequate assessment of more recent agents require longer observation periods.References[1]Choquette, D., Bessette, L., Alemao, E.et al. Arthritis Res Ther21, 138 (2019).[2]Lopatina E, Marshall DA, Coupal L, Le Lorier J, Choquette D. Curr Med Res Opin. 2021 Jan;37(1):157-166.Table 1.Characteristics of selected patients at TIVariableOMA (N=291)TNFi (N=320)P-ValueAge at diagnosis, years43.9 ± 14.8 (N=291)44.5 ± 14.4 (N=320)0.6324¹Disease duration at TI, years12.9 ± 10.4 (N=291)14.1 ± 11.1 (N=320)0.1741¹Women, n (%)236 (81.1%)233 (72.8%)0.0166²ACCI2.1 ± 1.7 (N=291)2.1 ± 1.7 (N=320)0.9498¹Hyperlipidemia3118 (40.6%)126 (39.4%)0.8042²Diabetes355 (18.9%)48 (15.0%)0.2340²Hypertension3160 (55.0%)171 (53.4%)0.7452²COPD3113 (38.8%)102 (31.9%)0.0755²CVD353 (18.2%)48 (15.0%)0.3265²Patient global, 1 to 10 visual analog scale [VAS]5.3 ± 2.6 (N=200)4.0 ± 2.8 (N=176)<.0001¹Patient pain, VAS5.8 ± 2.8 (N=200)4.3 ± 3.0 (N=176)<.0001¹Patient fatigue, VAS5.5 ± 2.9 (N=200)4.1 ± 3.2 (N=176)<.0001¹Duration of morning stiffness, minutes124.6 ± 284.1 (N=201)71.7 ± 215.7 (N=175)0.0451¹HAQ score1.4 ± 0.6 (N=202)1.1 ± 0.7 (N=176)<.0001¹Physician global assessment, VAS4.6 ± 2.7 (N=138)2.9 ± 2.5 (N=121)<.0001¹Swollen joint count,/28 joints8.0 ± 5.2 (N=165)4.9 ± 6.0 (N=142)<.0001¹Tender joint count,/28 joints7.2 ± 6.0 (N=165)4.3 ± 5.6 (N=142)<.0001¹RF, ever positive194 (69.8%)200 (65.4%)0.2887²ACPA, ever positive168 (62.9%)168 (61.1%)0.7234²ESR at TI, mm/hr26.9 ± 23.5 (N=211)21.6 ± 18.2 (N=183)0.0136¹CRP at TI, mg/L15.4 ± 23.0 (N=224)8.9 ± 14.4 (N=211)0.0005¹Continuous data are presented as mean ± standard deviation (N=X), where X represents the number of non-missing data points, and categorical data are expressed as n (%). P-values are based on1pooled variance t-test or2Fisher’s exact tests.3The presence of comorbidity is based on an established diagnosis and/or comorbidity-specific drug use.Figure 1.Acknowledgements:NIL.Disclosure of InterestsDenis Choquette Speakers bureau: Abbvie, Amgen, Eli Lilly, Fresenius Kabi, Novartis, Pfizer, Sandoz, Tevepharm, Consultant of: Abbvie, Amgen, Eli Lilly, Fresenius Kabi, Novartis, Pfizer, Sandoz, Tevepharm, Grant/research support from: Abbvie, Amgen, Eli Lilly, Fresenius Kabi, Novartis, Pfizer, Sandoz, Tevepharm, Louis Bessette Speakers bureau: Abbvie, Amgen, BMS, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, Sandoz, Tevepharm, UCB, Consultant of: Abbvie, Amgen, BMS, Celgene, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, Sandoz, Sanofi-Genzyme, Tevepharm, UCB, Grant/research support from: Abbvie, Amgen, BMS, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, Sandoz, Sanofi-Genzyme, UCB, Loïc Choquette Sauvageau: None declared, Jacques Brown Speakers bureau: Amgen, Janssen, Consultant of: Amgen, Gilead, Paladin, Pfizer, Ultragenyx, Isabelle Ferdinand Speakers bureau: Pfizer, Consultant of: Abbvie, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, UCB, Paul Haraoui Speakers bureau: Pfizer, Consultant of: Abbvie, Amgen, Lilly, Pfizer, Sandoz, UCB, Grant/research support from: Abbvie, Amgen, Pfizer, UCB, Maxine Joly-Chevrier: None declared, Ariel Masetto Speakers bureau: Abbvie, Janssen, Novartis, Pfizer, Consultant of: Abbvie, Janssen, Novartis, Pfizer, Sanofi-Genzyme, UCB, Grant/research support from: Novartis, Frédéric Massicotte Speakers bureau: Jansen, Consultant of: Abbvie, Eli Lilly, Janssen, Pfizer, Valerie Nadon Consultant of: Abbvie, Eli Lilly, Janssen, Pfizer, Roche, Sanofi-Genzyme, Jean-Pierre Pelletier Shareholder of: ArthroLab Inc., Consultant of: TRB Chemedica SA, Grant/research support from: TRB Chemedica SA, Jean-Pierre Raynauld Speakers bureau: Abbvie, Amgen, BMS, Eli Lilly, Janssen, Novartis, Pfizer, Sandoz, Sanofi-Genzyme, Consultant of: Abbvie, ArthroLab Inc., Janssen, Pfizer, Sanofi-Genzyme, Diane Sauvageau: None declared, Angèle Turcotte: None declared, Édith Villeneuve Speakers bureau: Abbvie, BMS, Novartis, Pfizer, Consultant of: Abbvie, Amgen, Novartis, Pfizer, Louis Coupal: None declared.
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Pileggi Vinha, Telma, et Luciene Regina Paulino Tognetta. « CONSTRUINDO A AUTONOMIA MORAL NA ESCOLA : OS CONFLITOS INTERPESSOAIS E A APRENDIZAGEM DOS VALORES ». Revista Diálogo Educacional 9, no 28 (7 juillet 2009) : 525. http://dx.doi.org/10.7213/rde.v9i28.3316.
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A partir de pesquisas que investigaram se o ambiente escolar influencia o desenvolvimento moral dos alunos e a maneira com a qual eles se relacionam e resolvem seus conflitos interpessoais, propõe-se uma reflexão, fundamentada na teoria construtivista, sobre a forma como os conflitos têm sido resolvidos na escola em duas perspectivas (tradicional e construtivista) e uma análise das consequências destes na formação moral dos alunos. Inicialmente é apresentado um breve quadro teórico que fundamenta essas investigações, descrevendo o desenvolvimento moral segundo a teoria de Jean Piaget e outros pesquisadores que compartilham dessa concepção, e são estabelecidas ISSN 1518-3483 Rev. Diálogo Educ., Curitiba, v. 9, n. 28, p. 525-540, set./dez. 2009 Licenciado sob uma Licença Creative Commons 526 VINHA, T. P.; TOGNETTA, L. R. P. Rev. Diálogo Educ., Curitiba, v. 9, n. 28, p. 525-540, set./dez. 2009 algumas reflexões sobre o ambiente sociomoral da escola e a construção da autorregulação. Constata-se que, apesar de os educadores afirmarem que pretendem favorecer a formação de pessoas autônomas que vivam relações mais justas, respeitosas e solidárias, nem sempre conseguem fazer com que as crianças e os jovens pautem suas ações em princípios morais e autorregulem seus comportamentos. Em seguida, são apresentados os principais processos utilizados para intervir nas situações de conflitos interpessoais tanto pelos educadores que possuem uma perspectiva tradicional quanto na construtivista, compreendendo que estes transmitem mensagens que dizem respeito à moralidade. Os resultados encontrados indicam que, apesar dos professores terem objetivos comuns, o processo empregado nas escolas mais tradicionais favorece a manutenção de altos níveis de heteronomia em seus alunos. Constatou-se ainda que, por causa da concepção de que os conflitos são naturais nas relações e podem ser oportunidades para trabalhar os valores e regras e ao emprego de intervenções mais coerentes com o processo de construção da moralidade, tais intervenções contribuíram mais efetivamente para a melhoria das relações interpessoais e para o desenvolvimento da autorregulação.
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Palmer, Christine D., Amy R. Rappaport, Meghan G. Hart, Lauren D. Kraemer, Sonia Kounlavouth, Martina Marrali, Jason R. Jaroslavsky et al. « Abstract 4159 : Lower doses of self-amplifying mRNA drive superior neoantigen-specific CD8 T cell responses in cancer patients versus high doses ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 4159. http://dx.doi.org/10.1158/1538-7445.am2022-4159.
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Abstract The immunogenicity and efficacy of RNA-based vaccine platforms has been abundantly shown through their application in prophylactic SARS-CoV2 vaccines. Contrasting to mRNA based vectors, self amplifying mRNA platforms may offer dose-sparing and superior induction of T cell responses, and may also trigger distinct innate immune pathways, which may exert adjuvanting or inhibiting effects on vaccine-induced immunity. Optimal dosing for a novel self-amplifying mRNA (SAM) in a heterologous prime-boost vaccination approach consisting of Chimpanzee Adenovirus (ChAd) prime and SAM boosts was evaluated in two first-in-human phase 1/2 clinical trials assessing personalized neoantigen vaccines in patients with metastatic cancer (NCT03639714, NCT03953235). SAM vaccine dose escalation was performed to assess safety, tolerability, and immunogenicity, including administration of up to 8 SAM doses at 30, 100, or 300µg following a fixed dose of ChAd (1012 vp) over the course of a year. SAM was safe and well tolerated at all 3 dose levels, with no evidence of increasing reactogenicity with sequential doses. However, while immune monitoring via IFNγ ELISpot revealed that the 30µg SAM dose boosted T cell responses induced by the ChAd prime, the 100µg and 300µg SAM doses resulted in maintenance of T cell levels, without a clear T cell boost, suggesting a non-linear and likely bell-shaped dose-response curve to SAM in humans. Follow-up studies in non-human primates (NHPs) using a model antigen revealed dose-dependent increases in serum IFNa levels following administration of increasing SAM doses. Similarly, while multiple inflammatory cytokines were transiently increased following both ChAd and SAM administration in patients, serum IFNa levels were only increased 24h post SAM administration and correlated positively with SAM dose. Increased IFNa levels post SAM dosing suggested activation of mRNA-sensing innate immune pathways that may reduce the amplification of, and/or antigen expression by, the SAM vector and thus blunt T cell boosting at higher SAM doses. In addition, analysis of T cell responses in patients and NHPs showed increased boosting of T cell responses with longer intervals. These data lead to a reduction of the SAM dose to 30µg and adjusting SAM dosing intervals to 8 weeks in the Phase 2 portion of these clinical studies. Multiple patients have been dosed with the adjusted vaccine regimen, and preliminary data suggest robust boosting of ChAd-induced neoantigen-specific T cell responses with the selected SAM dosing regimen and the 30µg dose. We anticipate that this translational approach of adjusting clinical vaccine regimens based on strong translational immune data will increase the potency of our heterologous neoantigen vaccine, and subsequently provide more durable clinical benefit to patients with cancer. Citation Format: Christine D. Palmer, Amy R. Rappaport, Meghan G. Hart, Lauren D. Kraemer, Sonia Kounlavouth, Martina Marrali, Jason R. Jaroslavsky, Charmaine N. Nganje, Annie Shen, Gregory R. Boucher, Melissa A. Kachura, Ciaran D. Scallan, Sue-Jean Hong, Leonid Gitlin, Alexander I. Spira, Chrisann Kyi, Daniel V. Catenacci, Raphael Rousseau, Andrew Ferguson, Karin Jooss. Lower doses of self-amplifying mRNA drive superior neoantigen-specific CD8 T cell responses in cancer patients versus high doses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4159.
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Guegan, Jean-Philippe, Florent Peyraud, Aurelien Marabelle, Nathalie Chaput, Dominique Bodet, Laure Fontan, Anthony Gaultier et al. « Abstract 1251 : Low plasma Arginine level is associated with resistance to immune checkpoint blockers in patients with advanced cancer ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 1251. http://dx.doi.org/10.1158/1538-7445.am2022-1251.
Texte intégralRésumé :
Abstract Background: The discovery of immune checkpoint blockers (ICB) has revolutionized the systemic approach of the treatment of cancer. However, most patients receiving ICB do not derive benefit. Therefore, there is a crucial need to identify reliable predictive biomarkers of response to anti-PD-1/PD-L1 agents, both to develop precision medicine in cancer immunotherapy and to better understand mechanisms of sensitivity and resistance. One pathway that plays an important role in the regulation of immune cell reactivity is L-Arginine (Arg) metabolism, which is essential to T-cell activation. We therefore aimed at evaluating the association of baseline plasmatic level of Arg - serving as a surrogate of Arginase (Arg1) activity - and clinical benefit to ICB. Methods: Correlation with Arg levels and efficacy of ICB in the pre-clinical setting was assessed by using a syngeneic mouse model of colorectal cancer (MC38) known to be responsive to ICB. Correlation of Arg levels and clinical activity of ICB was assessed by analyzing the plasma samples obtained before treatment onset in two independent cohorts of patient with advanced cancer and included in two institutional molecular profiling programs (discovery cohort: BIP, NCT02534649, n=77; validation cohort: PREMIS, n=295, NCT03984318). In addition, using matched PBMCs-plasma samples, we analyzed the correlation between Arg level and features of PBMCs that were captured through multiplexed-flow cytometry analysis. Results: As expected, treatment of MC38-tumor bearing mice with anti-PD(L)1 antibodies demonstrated a strong anti-tumor effect with tumor rejection observed for app. 40% of mice (11 out of 28). The tumor rejection rate was significantly higher in mice with high baseline Arg level than in mice with low Arg level: 85.7% versus 23.8%, p=0.004. In both discovery and validation cohorts, low Arg level at baseline (42 <µmol/L) was significantly associated with worse clinical benefit rate, progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that low baseline Arg level isd an independent prognostic factor for both PFS and OS. Finally, PBMCs immunophenotyping showed that low Arg level was significantly associated with increased PDL1 expression in several immune cell subsets from the myeloid lineage. Conclusions: Altogether, our results demonstrate that baseline Arg levels are highly predictive of ICB efficacy. Increase in PDL1 expression in myeloid cells upon Arg deprivation could partly underly its suppressive activity. Plasmatic Arg quantification can therefore represent an attractive biomarker to tailor novel therapeutic regimens targeting the Arginase pathway in combination with ICB. Citation Format: Jean-Philippe Guegan, Florent Peyraud, Aurelien Marabelle, Nathalie Chaput, Dominique Bodet, Laure Fontan, Anthony Gaultier, Imane NAFIA, Francois-Xavier Danlos, David Planchard, Caroline Robert, Caroline Even, Mohamed Khettab, Lambros Tselikas, Luc Friboulet, Jean-Charles Soria, Fabrice Andre, Fabrice Barlesi, Alban Bessede, Antoine Italiano. Low plasma Arginine level is associated with resistance to immune checkpoint blockers in patients with advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1251.
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Caillard, Olivier, Heather A. McLean, Yehezkel Ben-Ari et Jean-Luc Gaïarsa. « Ontogenesis of Presynaptic GABAB Receptor-Mediated Inhibition in the CA3 Region of the Rat Hippocampus ». Journal of Neurophysiology 79, no 3 (1 mars 1998) : 1341–48. http://dx.doi.org/10.1152/jn.1998.79.3.1341.
Texte intégralRésumé :
Caillard, Olivier, Heather A. McLean, Yehezkel Ben-Ari, and Jean-Luc Gaı̈arsa. Ontogenesis of presynaptic GABAB receptor-mediated inhibition in the CA3 region of the rat hippocampus. J. Neurophysiol. 79: 1341–1348, 1998. γ-Aminobutyric acid-B(GABAB) receptor-dependent and -independent components of paired-pulse depression (PPD) were investigated in the rat CA3 hippocampal region. Intracellular and whole cell recordings of CA3 pyramidal neurons were performed on hippocampal slices obtained from neonatal (5–7 day old) and adult (27–34 day old) rats. Electrical stimulation in the hilus evoked monosynaptic GABAA postsynaptic currents (eIPSCs) isolated in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 μM) and d(−)2-amino-5-phosphovaleric acid (d-AP5, 50 μM) with 2(triethylamino)- N-(2,6-dimethylphenyl) acetamine (QX314) filled electrodes. In adult CA3 pyramidal neurons, when a pair of identical stimuli was applied at interstimulus intervals (ISIs) ranging from 50 to 1,500 ms the amplitude of the second eIPSC was depressed when compared with the first eIPSC. This paired-pulse depression (PPD) was partially blockedb y P - 3 - a m i n o p r o p y l - P - d i e t h o x y m e t h y l p h o s p h o r i c a c i d(CGP35348, 0.5 mM), a selective GABAB receptor antagonist. In neonates, PPD was restricted to ISIs shorter than 200 ms and was not affected by CGP35348. The GABAB receptor agonist baclofen reduced the amplitude of eIPSCs in a dose-dependent manner with the same efficiency in both adults and neonates. Increasing the probability of transmitter release with high Ca2+ (4 mM)/low Mg2+ (0.3 mM) external solution revealed PPD in neonatal CA3 pyramidal neurons that was 1) partially prevented by CGP35348, 2) independent of the membrane holding potential of the recorded cell, and 3) not resulting from a change in the reversal potential of GABAA eIPSCs. In adults the GABA uptake blocker tiagabine (20 μM) increased the duration of eIPSCs and the magnitude of GABAB receptor-dependent PPD. In neonates, tiagabine also increased duration of eIPSCs but to a lesser extent than in adult and did not reveal a GABAB receptor-dependent PPD. These results demonstrate that although GABAB receptor-dependent and -independent mechanisms of presynaptic inhibition are present onGABAergic terminals and functional, they do not operate at the level of monosynaptic GABAergic synaptic transmission at early stages of development. Absence of presynaptic autoinhibition of GABA release seems to be due to the small amount of transmitter that can access presynaptic regulatory sites.
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LACAZE, Jean Louis, Clémence Brac de la Perrière, Mony Ung, Florence Dalenc, Vincent Nicolai, Eleonore De Maio, Marion Montastruc et al. « Abstract P1-05-25 : Clinical and biological features of 158 consecutive and unselected oligometastatic breast cancers ». Cancer Research 83, no 5_Supplement (1 mars 2023) : P1–05–25—P1–05–25. http://dx.doi.org/10.1158/1538-7445.sabcs22-p1-05-25.
Texte intégralRésumé :
Abstract Background: In order to determine the optimal treatment strategy for oligometastatic breast cancer (OMBC), effective and safe treatments for metastatic sites and sensitive and specific imaging techniques are needed. But it is also essential to know the incidence of oligometastatic breast cancer and its clinical and biological characteristics [1]. Efficient imaging techniques and therapeutic tools exist, but knowledge of incidence, clinical and biological characteristics of OMBC is scarce. This is partly due to the lack of publications describing these data on recent, consecutive, and unselected series of OMBC. Methods: we retrospectively collected data from 998 patients diagnosed with synchronous or metachronous metastatic breast cancer (MBC) between January 2014 and December 2018 at our institution. The only criterion used to define OMBC was the presence of one to five metastases at diagnosis. Hormone receptor (HR) and HER2 receptor status, histology, SBR grade, number of metastases and organs affected were collected. Results: Of 998 MBC, 15.8% were OMBC (158/998). Among the series, 88% (139/158) of OMBC had 1 to 3 metastases and 86.7% (137/158) had only one organ involved. Among 158 patients, 52.5% (n=83) had bone metastases, 20.9% (n=33) had lymph node metastases, 14.6% (n=23) had liver metastases, 13.3% (n=21) had brain metastases, 8.2% (n=13) had lung metastases, and 3.8% (n=6) had others (skin, pancreas, adrenal). Among these 158 patients, 83.4% (n=131) had ductal breast carcinoma, 55.7% (n=88) had HR+/HER2- OMBC, 25.3% (n=40) had HER2+ OMBC and 19% (n=30) had HR-/HER2- OMBC. HR+/HER2- subtype was statistically associated with bone and bone only metastases (p=0.001), HER2+ subtype with brain metastases (p=0.001) and HR-/HER2- subtype with lymph node metastases (p=0.008). Visceral metastases (lung or liver) are not statistically associated with any biological subtypes. The proportion of OMBC with SBR grade III was statistically higher than in a series of 22,109 patients with MBC [2] (49.4% vs 35.2%; p< 0.001). Conclusion: OMBC is a heterogeneous entity. OMBC incidence is certainly much higher than the commonly used values. OMBC is not an indolent disease, and each subgroup, according to its biological and anatomical characteristics, may deserve a specific management. [1] Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol Off J Am Soc Clin Oncol 1995;13:8–10. https://doi.org/10.1200/JCO.1995.13.1.8. [2] Deluche E, Antoine A, Bachelot T, Lardy-Cleaud A, Dieras V, Brain E, et al. Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008–2016. Eur J Cancer 2020;129:60–70. https://doi.org/10.1016/j.ejca.2020.01.016. Citation Format: Jean Louis LACAZE, Clémence Brac de la Perrière, Mony Ung, Florence Dalenc, Vincent Nicolai, Eleonore De Maio, Marion Montastruc, Bastien Cabarrou, Nils Monselet, Ciprian Chira, Gauthier Glemarec, Thibaut Cassou-Mounat. Clinical and biological features of 158 consecutive and unselected oligometastatic breast cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-25.
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Vanacker, Helene, Mehdi Brahmi, Yannick Le Meitour, Julien Bollard, Valery Attignon, Alexandra Meurgey, Myriam Jean-Denis et al. « Abstract 6071 : Whole-exome RNA sequencing of metastatic synovial sarcomas reveals heterogeneous transcriptomic profile and targetable co-alterations : Cohort study from the French Sarcoma Group ». Cancer Research 83, no 7_Supplement (4 avril 2023) : 6071. http://dx.doi.org/10.1158/1538-7445.am2023-6071.
Texte intégralRésumé :
Abstract Introduction: Synovial Sarcoma (SS) is a rare and aggressive disease that predominantly occurs in young adult. SS are characterized by a pathognomonic t(X:18) translocation leading SS18: SSX1/2/4 fusion. Small studies (n<100) described molecular background beyond this fusion in patients and the transcriptomic profile of SS remains poorly known. The aim of our study is to provide a large cohort analyzing transcriptomic and co-alterations to better understand and treat SS. Methods: We present a clinico-biological cohort study including all adult patients with histologically confirmed diagnosis of afvanced SS from January 2000, registered in the French Sarcoma database (NETSARC+) and with available formalin-fixed paraffin embedded (FFPE) archival tumor samples and clinical data. FFPE tumor samples were analyzed by dedicated whole-exome RNA-sequencing (WERS) to assess transcriptomic, small nucleotide variation (SNV) and fusions. Results: 122 patients (133 samples) met the study criteria, including 11 patients with paired primary-metastatic tumor samples. Clinical characteristics (age, sex, tumor grade, primary and metastasis site distribution) were consistent with expected SS population. The SS18:SSX1/2/4 fusion was found in all patient (90% by WERS and if negative, by FISH). Unsupervised analyses of transcriptomic data by principal component analyses, hierarchical sample clustering or UMAP revealed heterogeneity in gene expression. Clinical factors (age, sex, grade, tumor type, complete response to treatment, survival) did not correlate with transcriptomic profiles. Immune cell analyses confirmed a low infiltration of immune cells, notably poor in CD8+ T cells. Cancer testis antigens such as NYESO-1, MAGE-A4 were both expressed with a heterogeneous co-expression of other CTAs across samples. In the 11 primary-metastatic paired- samples, no gene pathway was found differentially expressed between primary and metastatic samples cohort with the exception of lung tissue specific genes. Comparing chemotherapy-naïve versus pre-treated samples did not identify differential expression of specific genes across samples. Single Nucleotide Variant analyses was reliable on 84% FFPE samples and revealed an overall low Tumor Mutational Burden with some samples harboring canonical oncogene pathogenic mutations of BTK, RAS, NF1, RB1 as well as in DNA repair pathway(15% spanning over ATM ATR,CHK2, BRCA1/2 PALB2 CHK2, FANCM, RAD51), PI3K pathways (PI3KCA E545K) and other poorly described in SS. Conclusion: Investigating the largest cohort of metastatic SS by whole-exome RNA-sequencing, revealed Synovial Sarcoma, usually classified as “simple genomic sarcoma” is a translocation-related sarcoma harboring heterogeneous transcriptomic and numerous SNV co-alterations including targetable mutations. Citation Format: Helene Vanacker, Mehdi Brahmi, Yannick Le Meitour, Julien Bollard, Valery Attignon, Alexandra Meurgey, Myriam Jean-Denis, Laurie Tonon, Shibani Pokras, Erika Klohe, Michael Nathenson, Kristin Blouch, Ioanna Eleftheriadou, Jean-Yves Blay, Franck Tirode, Armelle Dufresne. Whole-exome RNA sequencing of metastatic synovial sarcomas reveals heterogeneous transcriptomic profile and targetable co-alterations: Cohort study from the French Sarcoma Group. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6071.
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Astier, Clémence, Jean-Yves Scoazec, Virginie Marty, Olivia Bawa, Nicolas Signolle, Carine Ngo, Francesco Facchinetti, Antoine Hollebecque et Sophie Postel-Vinay. « Abstract 5714 : Characterization of SWI/SNF complex gene mutations, protein expression and tumor immune microenvironment in cholangiocarcinoma ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 5714. http://dx.doi.org/10.1158/1538-7445.am2022-5714.
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Abstract Introduction: Cholangiocarcinoma (CCA) is a rare tumor accounting for less than 2% of all human malignancies. Mutations in the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex have been identified in approximately 20% of all human cancers and more than 40% of CCA. If the role of SWI/SNF on the tumor biology and microenvironment is being uncovered in other tumor types, it remains vastly unknown in CCA. Here, we wanted to investigate, using clinical samples, the association between SWI/SNF defects, the molecular landscape and tumor immune microenvironment in CCA. Material and Methods: Mutation profiling of 103 patients with CCA from Gustave Roussy (GR) was assessed with FoundationOne® CDx 324-gene NGS panel. Formalin-fixed paraffin-embedded tumor tissues from 11 patients with CCA were analyzed for SWI/SNF (PBRM1, ARID1A, SMARCB1 and SMARCA4) and Polycomb-DUB (BAP1) subunits, as well as lymphocytic markers (CD4 and CD8). Stainings were performed using a VENTANA BenchMark ULTRA. Absolute count of positive cells per mm2 was determined by digital image analysis with the Definiens Developer XD™ by selecting at least 5 independent tumoral zones. Pairwise comparisons were performed using the Mann-Whitney test. Results: Among the patients for whom NGS data was available, the most frequently altered genes were TP53 (27%), CDKN2A (17%), KRAS (16%), ARID1A (12%), FGFR2 (12%) and PBRM1 (10%). Subunits of the SWI/SNF complex and BAP1 were mutated in 25% and 10% of cases, respectively. Tumor samples with ARID1A mutations (n=5) showed strongly decreased ARID1A expression compared to WT tumor samples (n=2) (mean = 308.03 positive nuclei (p.n)/mm2 versus 6096.82 p.n/mm2 respectively; P<0.0001) but unchanged PBRM1, SMARCB1 and SMARCA4 expression. PBRM1 mutations (n=4) were associated with decreased expression of PBRM1 (mean = 309.6 p.n/mm2 versus 4980.2 p.n/mm2 in WT samples; P<0.0001) and ARID1A (mean=1196.15 p.n/mm2; P<0.001), but unchanged SMARCB1 and SMARCA4 expression. BAP1 mutations (n=3) were also associated with decreased BAP1 and ARID1A expression (ARID1A mean = 457.70 p.n/mm2; P<0.001). ARID1A and PBRM1-altered tumor samples showed a poorly infiltrated microenvironment, with decreased CD4+ T cell (159.48 positive cells (p.c)/mm2 and 188.66 p.c/mm2 respectively versus 1126.52 p.c/mm2 for WT; P<0.0001) and CD8+ T cell density (72.38 and 76.54 p.c/mm2 versus 548.58 p.c/mm2 for WT; P<0.0001). Conclusion: Mutations in the ARID1A and PBRM1 subunits of the SWI/SNF complex are associated with a loss of protein expression. In contrast to what reported in other tumor types, ARID1A and PBRM1 mutations correlated with poorly lymphocytic TIME in CCA. Decreased PBRM1 expression is further associated with decreased ARID1A expression. Independent revalidation and further study in larger tumor series are warranted. Citation Format: Clémence Astier, Jean-Yves Scoazec, Virginie Marty, Olivia Bawa, Nicolas Signolle, Carine Ngo, Francesco Facchinetti, Antoine Hollebecque, Sophie Postel-Vinay. Characterization of SWI/SNF complex gene mutations, protein expression and tumor immune microenvironment in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5714.