Academic literature on the topic 'Lien L1'

Plusieurs pays africains francophones subsahariens ont opté pour un bi-plurilinguisme scolaire langues nationales/français avec comme objectif principal de développer chez les élèves du primaire un bilinguisme fonctionnel. Le Mali ayant une longue tradition dans le domaine de l’enseignement bilingue langues nationales – français ne fait pas exception à la règle. Mais l’épine dorsale de l’enseignement bilingue demeure le transfert des apprentissages entre la langue première L1 et la langue seconde L2. La maîtrise par les enseignants des techniques visant à créer le rapport des deux langues où les connaissances apprises dans la première langue sont réinvesties comme tremplin pour acquérir facilement et rapidement la seconde langue a toujours été une préoccupation majeure. Fort de ce constat, la nécessité d’élaborer des fiches pédagogiques de transfert de compétences linguistiques L1 - L2 s’impose inéluctablement à l’éducation nationale. L’objectif de notre étude est de montrer la démarche qui à consister à produire une quarantaine de fiches de transferts dans le cadre d’un projet de l’Initiative ELAN en partenariat avec la Direction Nationale de l’Enseignement Fondamentale du Mali. La démarche méthodologique consiste à mettre face à face les différentes parties identiques pour permettre aux élèves de recourir à l’observation, à la comparaison et à l’analyse en vue de faire ressortir les ressemblances et les divergences dans les deux langues. L’Equipe qui a piloté le projet au niveau national s’est focalisée sur le niveau III du curriculum bilingue national de l’enseignement fondamental, autrement dit les classes de 5ème et 6ème année du primaire. Pour tenir compte de la progression dans les apprentissages, tous les contenus identifiés ont été rattachés à leur Unité d’Apprentissage dans le curriculum bilingue national. Ce qui permet aux enseignants de comprendre plus facilement le lien entre la fiche transfert et la fiche de séquence du curriculum

Plusieurs pays africains francophones subsahariens ont opté pour un bi-plurilinguisme scolaire langues nationales/français avec comme objectif principal de développer chez les élèves du primaire un bilinguisme fonctionnel. Le Mali ayant une longue tradition dans le domaine de l’enseignement bilingue langues nationales – français ne fait pas exception à la règle. Mais l’épine dorsale de l’enseignement bilingue demeure le transfert des apprentissages entre la langue première L1 et la langue seconde L2. La maîtrise par les enseignants des techniques visant à créer le rapport des deux langues où les connaissances apprises dans la première langue sont réinvesties comme tremplin pour acquérir facilement et rapidement la seconde langue a toujours été une préoccupation majeure. Fort de ce constat, la nécessité d’élaborer des fiches pédagogiques de transfert de compétences linguistiques L1 - L2 s’impose inéluctablement à l’éducation nationale. L’objectif de notre étude est de montrer la démarche qui à consister à produire une quarantaine de fiches de transferts dans le cadre d’un projet de l’Initiative ELAN en partenariat avec la Direction Nationale de l’Enseignement Fondamentale du Mali. La démarche méthodologique consiste à mettre face à face les différentes parties identiques pour permettre aux élèves de recourir à l’observation, à la comparaison et à l’analyse en vue de faire ressortir les ressemblances et les divergences dans les deux langues. L’Equipe qui a piloté le projet au niveau national s’est focalisée sur le niveau III du curriculum bilingue national de l’enseignement fondamental, autrement dit les classes de 5ème et 6ème année du primaire. Pour tenir compte de la progression dans les apprentissages, tous les contenus identifiés ont été rattachés à leur Unité d’Apprentissage dans le curriculum bilingue national. Ce qui permet aux enseignants de comprendre plus facilement le lien entre la fiche transfert et la fiche de séquence du curriculum

Économistes et banquiers centraux se sont interrogés sur la responsabilité des entreprises dans l'envolée de l'inflation en 2022-2023. En augmentant leurs prix de vente, les entreprises auraient contribué à la propagation, voire à l'amplification du choc de coût. Sur une longue période, des évolutions structurelles ont pu renforcer le rôle des entreprises (par opposition à celui des salariés) dans la dynamique de l'inflation, mais, à court terme, le lien entre pouvoir de marché des entreprises et transmission des chocs de coût est ambigu. Des entreprises plus puissantes facturent, certes, des prix plus élevés, mais elles ont aussi une plus grande capacité à absorber des chocs temporaires. Au total, une « boucle prix-profits » s'est bien matérialisée en 2002-2023, mais elle semble avoir été un phénomène temporaire, moins marqué en France qu'ailleurs en Europe. En 2024 et au-delà, alors que les prix de l'énergie se normalisent, que les salaires accélèrent et que l'inflation revient progressivement vers 2 %, il conviendra de suivre avec attention la normalisation des taux de marge des entreprises et d'éviter des rigidités à la baisse qui entretiendraient l'inflation. La politique de la concurrence peut jouer un rôle utile en identifiant les rentes sectorielles et en sanctionnant les comportements susceptibles d'amplifier la hausse des prix. Classification JEL : E31, E64, L1.

Im Mai 2017 ließ die amerikanische Arzneimittelbehörde FDA den PD-L1-Checkpoint-Inhibitor Durvalumab mit dem Status “Breakthrough-Therapy Designation” in einem beschleunigten Verfahren für fortgeschrittene Blasenkarzinome zu. Der monoklonale PD-L1-Inhibitor war bei progredienten Patienten mit einem Urothelkarzinom im Stadium IV wirksam. In der Phase I/II-Studie betrug das 1-Jahres-Überleben 55 % und übertraf damit historische Kontrollen. Der Therapieerfolg war mit der PD-L1-Expression assoziiert.

Acquisition by Processing Theory (APT) is a unified account of language processing and learning that encompasses both L1 and L2 acquisition. Bold in aim and broad in scope, the proposal offers parsimony and comprehensiveness, both highly desirable in a theory of language acquisition. However, the sweep of the proposal is accompanied by an economy of description that makes it difficult to evaluate the validity of key learning claims, or even how literally they are to be interpreted. Two in particular deserve comment; the first concerns the learning mechanisms responsible for adding new L2 grammatical information, and the second the theoretical and empirical status of the activation concept used in the model.

The primary aim of my target article was to demonstrate how careful consideration of the working memory operations that underlie successful language comprehension is crucial to our understanding of the similarities and differences between native (L1) and non-native (L2) sentence processing. My central claims were that highly proficient L2 speakers construct similarly specified syntactic parses as L1 speakers, and that differences between L1 and L2 processing can be characterised in terms of L2 speakers being more prone to interference during memory retrieval operations. In explaining L1/L2 differences in this way, I argued a primary source of differences between L1 and L2 processing lies in how different populations of speakers weight cues that guide memory retrieval.

This paper was aimed at addressing the topic of communicative styles of deception. University students were asked to describe a picture with varying truth/lie conditions. In accordance with their perception or being deliberately against it, the participant could: tell the truth (T); lie to an acquiescent recipient (L1); or lie to a suspicious recipient (L2). The goal was to investigate whether or not different linguistic styles could be correlated to the cognitive complexity of the task as regards the truth bias or lie bias of the recipient. Specifically, two sets of linguistic aspects – micro and macro structural – were analyzed. In the former, indices were considered as words (arguments number, repetitions and interruptions, fluency and fluency disorder indices), predicates (number, nominal/predicative construction, and personal/impersonal structure), pronouns and adverbial forms. In the latter, the structural variations of the standard phrase, utterances' complexity, spatial organization of utterances, and speech organization were analyzed. Results showed that participants used speech to shield from reality and chose different strategies; in the L1 condition, participants resorted to ambiguity and prolixity (“cuttlefish effect”); on the contrary, in the L2 condition they used concise assertiveness and elliptic eluding strategies (“chameleon effect”).

The current landscape of English language teaching are moving from the monolingual assumption to the understanding that L1 is part of one person’s whole linguistic repertoire. However, this shift is still largely occurring in research while the practice of English teaching still largely considers L1 to be an unwanted interference. The potential role of L1 in making the input comprehensible should receive further consideration. This essay will discuss how language teachers should seek to leverage students’ L1-encoded prior knowledge rather than viewing it as an impediment within the context of Content and Language Integrated Learning (CLIL) and translanguaging because they both explicitly affirm the goal of multilingual competence and involve the use of L1 in teaching practices. The difference lies in terms of the attitudes; the use of L1 is not contemplated as a priori in CLIL yet encouraged in translanguaging. This essay highlights the need for balanced and flexible L1 use in their respective contexts and pedagogies in respect to its roles: (1) L1 can negotiate meaning for L2 learning objects, (2) L1 can address the negative transfer of false cognates, (3) L1 can encourage the engagement of multilingual resources, and (4) L1 can facilitate classroom engagement.

Ce travail de thèse s'inscrit dans les domaines de la linguistique de l'acquisition, de la sociolinguistique et de la didactique des langues. Il s'agit d'une recherche-action qui vise à mieux appréhender l'acquisition du langage chez des enfants bilingues émergents de 3 à 5 ans, c'est-à-dire l'appropriation simultanée et/ou consécutive de deux langues, dans le contexte d'une école maternelle située en éducation prioritaire et dont le public est multilingue (une vingtaine de langues premières). L'objectif de la recherche consiste à observer comment l'enfant peut s'appuyer sur des compétences déjà construites en langue première pour construire des compétences en langue seconde. Le corpus est composé de plusieurs types de données : - un « corpus de travail » multilingue constitué d'outils pédagogiques dans lesquels figurent des traductions audios réalisées grâce à la collaboration des parents; - des captations vidéos d'interactions enfant/adulte permettant d'observer l'appropriation des éléments linguistiques proposés dans les supports; - des enregistrements réalisés tout au long du processus et visant à éclairer les parcours langagiers singuliers des élèves: séances de traductions, entretiens avec les parents, activités en classe.L'analyse qualitative de dix études de cas montre que : - concernant les enfants qui acquièrent le français comme L2, l'utilisation en classe de la L1 favorise leur engagement, ainsi que la compréhension et l'appropriation d'éléments linguistiques de la L2 ; - dans le cas des enfants qui ont deux L1 dont le français, la valorisation de la langue héritée encourage son développement
This thesis is part of linguistics of language acquisition, sociolinguistics and language education. It is a practical research that aims to understand language acquisition by emergent bilingual children from 3 to 5 years old, i.e. the simultaneous and / or consecutive acquisition of two languages, in the context of a kindergarten in priority education and whose public is multilingual (almost twenty first languages). The aim of the research is to observe how the child can rely on skills already acquired in the first language (L1) to build second language (L2) skills. The corpus is composed of several types of data: - a multilingual "corpus of work" consisting of educational tools in which audio translations are produced with the collaboration of the parents; - video recordings of child / adult interactions to observe the acquisition of the linguistic elements proposed in the supports; - recordings made throughout the process in order to highlight in what particular way students build their own language: translation sessions, interviews with parents, classroom activities.Qualitative analysis in ten case studies shows that : - in the case of children who acquire French as their L2, the use of the L1 in class forsters their engagement, as well as the comprehension and appropriation of linguistic elements from the L2 ; - in the case of children who have two L1s, including French, valuing the heritage language encourages its development

L’élément L1 (Long Interspersed Nuclear Element 1 ou L1) est le seul rétrotransposon autonome et actif connu dans notre génome, représentant 17% de celui-ci. Capable de se répliquer grâce à un intermédiaire à ARN et un mécanisme de transcription inverse initiée au site d’intégration, il encode deux protéines ORF1p et ORF2p, qui s’associent à l’ARN L1 pour former une particule ribonucléoprotéique (RNP). L’élément L1 rétrotranspose préférentiellement en cis : un L1 défectif est complémenté en trans par un élément fonctionnel de façon inefficace. Ce travail s'intéresse à deux étapes clefs du cycle réplicatif du L1 : l'assemblage de la RNP L1 en cis ou en trans afin d’explorer le mécanisme de la cis-préférence et la spécificité de l’initiation de la reverse transcription initiée. Nous avons d’abord comparé deux méthodes d’analyse de l’activité RT. Puis, nous avons montré l’importance de la complémentarité entre queue poly(A) de l’ARN L1 et site d’intégration durant l’initiation de la RT, ainsi que l’impact de mésappariements terminaux éventuels. Enfin, nous avons étudié les bases biochimiques de la cis-préférence, à travers la coexpression et la purification de deux éléments distincts étiquetés, ce qui nous a permis de suivre l'assemblage et l'activité de leurs RNPs respectives. Nos données suggèrent que ORF1p et ORF2p peuvent lier en trans l’ARN L1 de façon efficace et que la cis-préférence pourrait nécessiter des quantités limitantes de L1
The Long Interspersed Nuclear Element 1 (LINE-1 ou L1) is the only known active and autonomous retrotransposon in the human genome and constitutes around 17% of our genomic DNA. The L1 element is able to replicate through an RNA intermediate by a mechanism called target-primed reverse transcription and encodes two proteins ORF1p and ORF2p, which associate with the L1 RNA to form a ribonucleoprotein particle (RNP). L1 preferentially retrotranspose in cis: a defective L1 can only be rescued in trans at low levels by a replication-competent copy. During this work, we focused on two essential steps of the L1 replication cycle: the assembly of the L1 RNP in cis or in trans to explore the mechanism of the cis-preference and the specificity of L1 reverse transcription priming. First, we compared two different methods to detect L1 RT activity. Then, we showed the importance of base-pairing between the poly(A) tail of the L1 RNA and the integration site to prime reverse transcription and the impact of potential mismatches. Finally, we investigated the biochemical basis of the cis-preference through the coexpression and purification of two different tagged L1 elements, which allowed us to follow the assembly and activity of their RNP. Our data suggest that binding of ORF1p and ORF2p in trans is efficient and that the cis-preference might requires limiting L1 levels

L’élément L1 (Long Interspersed Nuclear Element 1 ou L1) est le seul rétrotransposon autonome et actif connu dans notre génome, représentant 17% de celui-ci. Capable de se répliquer grâce à un intermédiaire à ARN et un mécanisme de transcription inverse initiée au site d’intégration, il encode deux protéines ORF1p et ORF2p, qui s’associent à l’ARN L1 pour former une particule ribonucléoprotéique (RNP). L’élément L1 rétrotranspose préférentiellement en cis : un L1 défectif est complémenté en trans par un élément fonctionnel de façon inefficace. Ce travail s'intéresse à deux étapes clefs du cycle réplicatif du L1 : l'assemblage de la RNP L1 en cis ou en trans afin d’explorer le mécanisme de la cis-préférence et la spécificité de l’initiation de la reverse transcription initiée. Nous avons d’abord comparé deux méthodes d’analyse de l’activité RT. Puis, nous avons montré l’importance de la complémentarité entre queue poly(A) de l’ARN L1 et site d’intégration durant l’initiation de la RT, ainsi que l’impact de mésappariements terminaux éventuels. Enfin, nous avons étudié les bases biochimiques de la cis-préférence, à travers la coexpression et la purification de deux éléments distincts étiquetés, ce qui nous a permis de suivre l'assemblage et l'activité de leurs RNPs respectives. Nos données suggèrent que ORF1p et ORF2p peuvent lier en trans l’ARN L1 de façon efficace et que la cis-préférence pourrait nécessiter des quantités limitantes de L1
The Long Interspersed Nuclear Element 1 (LINE-1 ou L1) is the only known active and autonomous retrotransposon in the human genome and constitutes around 17% of our genomic DNA. The L1 element is able to replicate through an RNA intermediate by a mechanism called target-primed reverse transcription and encodes two proteins ORF1p and ORF2p, which associate with the L1 RNA to form a ribonucleoprotein particle (RNP). L1 preferentially retrotranspose in cis: a defective L1 can only be rescued in trans at low levels by a replication-competent copy. During this work, we focused on two essential steps of the L1 replication cycle: the assembly of the L1 RNP in cis or in trans to explore the mechanism of the cis-preference and the specificity of L1 reverse transcription priming. First, we compared two different methods to detect L1 RT activity. Then, we showed the importance of base-pairing between the poly(A) tail of the L1 RNA and the integration site to prime reverse transcription and the impact of potential mismatches. Finally, we investigated the biochemical basis of the cis-preference through the coexpression and purification of two different tagged L1 elements, which allowed us to follow the assembly and activity of their RNP. Our data suggest that binding of ORF1p and ORF2p in trans is efficient and that the cis-preference might requires limiting L1 levels

This thesis provides a literature review on various topics related to the aims of the research project. In the process of sketching the rationale of this study, the language-in-education policy (LiEP) of South Africa is examined. The reasons why this policy is not successful, is discussed. Emanating from this discussion, the low literacy scores amongst young learners in South Africa are described and possible reasons for this occurrence are cited (Howie, Van Staden, Tshele, Dowse, & Zimmerman, 2012). The hypothesis that perceptual and articulation training of the vowels of English would enhance young English second language (Setswana first language-speaking) learners? awareness of English vowels, is posited and defended by referring to previous research (Moats, 2007; Trehearne, 2011; Seeff-Gabriel, 2003). In addition, it is stated that increased knowledge of the vowel system of English will improve English second language (EL2) learners? literacy skills (Moats, 2007). In order to explain and discuss the results of the investigations into the literacy skills of the EL2 learners participating in this study, the notions of literacy acquisition, phonological awareness skills, and language acquisition and language learning are examined. The main aim of this study is to assess the effects of intervention on the auditory perception and articulatory skills of English second language-speaking (EL2) (Setswana L1-speaking) learners in Grade 3, in the production of the monophthongs and diphthongs of the standard variety of South African English, namely White South African English (WSAfE) (Bekker, 2009). The effects are determined by acoustically comparing the vowel spaces of the participants before and after intervention. Therefore, a discussion of acoustic concepts such as the vowel space and the parameters thereof are provided. In addition, the vowels of WSAfE, those of Black South African English (BSAE), and the vowels of Setswana are discussed and compared according to their acoustic features. The results of this quasi-experimental, comparative study indicate that the vowel spaces of the EL1 and EL2 participants differ markedly before intervention, especially when comparing those of the short and long monophthongs of English. After intervention, the vowel spaces of especially the Experimental group are seen to approximate those of the EL1 participants in the Norm group. Interesting findings concerning the central schwa vowels and the diphthongs were made. These indicate that young EL2 (Setswana L1-speaking) learners do not use BSAE, but use a new? variety of English that is closer to WSAfE (Mesthrie, 2008). Pertaining to the measurable sub-aims of this study, the phonological awareness skills and literacy skills of the participants are assessed and compared, before and after intervention. The improvement of the phonological awareness skills and literacy skills of the Experimental group, as well as the changes in the vowel spaces that are noted for this group, prove the hypothesis that intervention in the form of additional input concerning the English vowels will enhance second language learners? perception and articulation. This strengthens the opinion that second language learners need quality teaching of the sound system of the language of learning and teaching.
Thesis (DPhil)--University of Pretoria, 2016.
African Languages
DPhil
Unrestricted

Gestures and speech are two interconnected features of human communication. Studies have shown that they develop together and they both covey semantic and pragmatic meanings (Kendon, 2004; McNeill, 1992). Furthermore, gestures seem to be also linked to the prosodic features of speech since they also share synchronicity aspects and are often temporally aligned (McClave, 1991; Esteve-Gibert & Prieto, 2013). The co-production of gestures and speech, thus, seems to have a number of different functions both at the cognitive and at the communicative levels. On the one hand, in fact, gestures seem to help the process of speaking: they have a scaffolding function in the lexical and rhythmical organization of speech and they help information packaging (Butterworth & Beattie, 1978; Esteve-Gibert et al., 2014; Krauss et al, 1996; Kita, 2000, 2010). This is supported by the evidence that speakers gesticulate also when they don’t see their addressees (for example when they are speaking over the phone (Cohen & Harrison, 1973; de Ruiter, 2003). On the other hand, gesturing is intended to communicate and is part of the speaker’s communicative effort (Kendon, 2004). Gestures also play an important role in L2 development and communicative strategies (Gullberg, 1998) and it is possible that L1 gestures influence gestures during L2 language development, and that gestural transfer co-occurs with linguistic transfer (Brown & Gullberg, 2008; Pika, Nicoladis, Marentette, 2006). It has also been suggested that, since gestures play an important role in facilitating language access in speech production, bilingual/L2 speakers may gesture more than monolingual speakers. This would be due to the cognitive load deriving from speaking a different language from the native one (Kita, 2000; Krauss & Hadar, 1999). Until now, gestures and prosody have been studied mostly in their temporal interaction and coordination (McClave, 1991, Loehr, 2004) or in the possible similarities between their pragmatic functions (Tuite, 1993). Little attention has been paid to the relationship between speakers’ global pitch range and use of gestures (and gesture categories) in conditions of high cognitive effort, or when they increase their communicative effort in their speeches. In fact, there seem to be a lack of scientific evidence about the use of pitch and gestures variability as a communicative strategy of the speaker. The aim of this thesis is to investigate aspects of the role and functions of gestures and speech in L1 and L2 and how the cognitive and communicative efforts may influence speakers’ global pitch range and the use of gestures in a story telling task. The investigation consists of two experiments. The first one (presented in chapter 5) aims to examine if speakers’ increase in the communicative effort produces changes in pitch variation and in the use of different categories of gestures. The second one (presented in chapter 6) examines the effects of speakers’ decrease in cognitive effort in the production of speech and gestures. In the first experiment 8 Italian speakers, Italian learners of English (L2) and students of a Public Speaking class, were asked to read and tell a fable in English to their classmates (Italian was used only as a control and recorded only one time). One week later, the subjects were asked to repeat the task with the instruction to be as communicative as possible. The audiovisual material was analyzed with the software Praat (phonetic analysis) and Elan (gesture analysis). For speech, the aim was to examine possible changes in the speakers’ fluency and pitch variation after they received the instruction to be communicative; for gestures, the aim was to examine the variations in both speakers’ overall gesturing and representational gestures in the communicative task. The hypothesis tested was that the communicative task causes an increase in fluency in the L2 (shown through features like a higher speech rate and a decrease of disfluencies and pauses), and that the communicative task leads to an increased use of representational gestures, since they might be considered as helpful for the addressee to better understand what is said. The results of the first experiment led to the conclusion that if a person is asked to be communicative in the L2, they will probably increase both their pitch variation and the total number of gestures produced, with a significant increase in iconic and representational gestures. The results on pitch variation, though, do not exclude the possible effect of other variables, first of all of task repetition. In fact, it is possible that by repeating the task, the speakers became more confident and could be more focused on being more communicative in telling the story. The second experiment tests the effect of task repetition on L2 speech and gesture. In this experiment (chapter 6) only the cognitive facilitation and the effect of the decrease in cognitive load was considered. This time, in fact, the subjects (10 Italian students of English L2) were asked to watch a short cartoon and to tell the story, both in Italian and English, in front of a small audience while being video-recorded. The subjects were asked to repeat the task one week later in the two languages with the same modalities. The analyses followed the same procedure as the previous experiment (chapter 5). The hypotheses tested were that repetition itself could influence the communicativeness of the speakers in both the speech and the gesturing levels, with an increased fluency and a different use of gestures compared to the first narration attempt. This could be caused by the facilitation of the task in terms of cognitive load and better memorization. The results showed that with the decrease of the cognitive load, speakers reach a higher fluency in L2. In Italian, however, the speakers show no significant difference in fluency or liveliness (Hincks, 2005) and this might be due to the fact that repetition and memorization did not help their fluency as much as they did in the L2. As for gestures, the speakers employed a greater number overall gestures when speaking English, their L2. The use of gestures, though, did not change in spite of the repetition, with a greater use of discursive gestures even if representational gestures seem to be used more in the L2 than in Italian. Overall, the investigation shows that the results of the two experiments can be integrated and offer a wider picture on the use of gesture and the employment of representationality with the conscious intent to be communicative. When people are asked to tell a story in a more communicative way, their response is to increase the representationality carried in their gestures and consequently use more representational gestures, this does not occur whenever the subjects only repeat the narration with a lighter cognitive load.
La comunicazione parlata è fortemente legata a quella gestuale. Il sistema gestuale e quello del parlato, infatti, sono considerati parti integranti di uno stesso sistema linguistico all’interno del quale si sviluppano assieme e si condizionano e influenzano l’un l’altro (Kendon, 2004; McNeill, 1992). I gesti, infatti, supportano l’organizzazione e “l’impacchettamento” delle informazioni espresse nel parlato (Information packaging, Kita 2000, Alibali & Kita, 2010). I gesti, inoltre, integrano e contribuiscono alla resa semantica e pragmatica del parlato (Kendon, 2004). Inoltre, la gestualità sembra ricoprire un ruolo anche per quanto riguarda alcuni aspetti ritmico prosodici del parlato, sia nella prima che nella seconda lingua (Esteve-Gibert & Prieto, 2014; McCafferty, 2004). Generalmente, gli studi che mettono in relazione prosodia e parlato si concentrano sulla sincronicità dei picchi intonativi con determinate categorie gestuali (generalmente i beats o batonici, caratterizzati da movimenti ritmici di dita, mani o braccia). Molta meno attenzione è stata data alla relazione esistente fra la variabilità intonativa e l’uso delle categorie gestuali. Mancano quindi studi che investighino il comportamento di gesti e prosodia in condizioni di comunicatività e sforzo cognitivo differente. Anche se diverse lingue hanno diverse caratteristiche prosodiche e intonative che le contraddistinguono, esistono comunque degli universali prosodici (Ladd, 2008) che caratterizzano il parlato e ne comunicano alcuni aspetti pragmatici (un universale prosodico, ad esempio, è l’alzarsi del contorno intonativo quando la frase viene interrotta da una pausa ma non è ancora considerata conclusa dal parlante). Per esempio, è stato dimostrato che la variabilità dell’intonazione influenza la percezione della vivacità del discorso (Hincks, 2004, 2005). Ne potrebbe essere una dimostrazione il fatto che, nei corsi di public speaking, gli studenti vengano incitati a modulare il tono di voce in modo tale che risulti variato. Un’altra istruzione che viene data agli studenti di public speaking riguarda la modulazione del proprio linguaggio del corpo e, quindi, della gestualità. Slemberebbe in fatti che anche la variabilità del linguaggio del corpo abbia come effetto la percezione di una maggiore vivacità comunicativa e aiuti quindi l’ascoltatore. Tuttavia, nel panorama della ricerca scientifica, scarseggiano gli studi che dimostrano l’esistenza una relazione tra la variabilità dell’intonazione e dei gesti del parlante. Una parte consistente del lavoro di questa tesi è infatti rivolto all’approfondimento della funzione comunicativa di gesti e intonazione e alla verifica di possibili correlazioni fra questi due aspetti. Un’altra questione che viene affrontata all’interno di questa tesi è l’effetto della ripetizione e la conseguente facilitazione del compito di narrazione in L2. Comunicare in una lingua straniera, infatti, comporta un complesso sforzo cognitivo: oltre a dover organizzare il discorso e recuperare il lessico adeguato, il parlante deve conferire al proprio discorso anche la pronuncia, la prosodia e il ritmo della lingua che sta parlando. Questo sforzo cognitivo può portare a una diminuzione della fluenza, ad un aumento di esitazioni nel parlato ed a una minore variabilità intonativa (Zimmerer et al. 2014). Un aspetto che verrà investigato all’interno di questo lavoro riguarda, appunto, il rapporto fra la facilitazione del compito narrativo in L2, attraverso la ripetizione del task narrativo, e l’uso di prosodia e gesti. Questa tesi si inserisce negli studi relativi a gesti e prosodia e si focalizza sulle differenze gestuali e prosodico-intonative in parlanti L2 di inglese che raccontano una favola e la ripetono poi a distanza di una settimana. L’ipotesi che ho voluto testare è che quando cambia il contesto comunicativo cambia anche la gestualità e alcuni aspetti ritmici e linguistici del parlato. In particolare, quando domina la funzione cognitiva del parlato, e quindi il soggetto si concentra sulla struttura della storia, prevalgono gesti di tipo ritmico-discorsivo anche associati alle esitazioni del parlante; quando invece domina la funzione comunicativa, aumentano i gesti di tipo rappresentativo e diminuiscono le esitazioni nel parlato. Il lavoro è strutturato in due parti: la prima parte, Theoretical Background, è intesa come la presentazione dell’argomento e della letteratura riguardante i temi d’interesse. La seconda parte riguarda i due esperimenti condotti per testare le ipotesi di ricerca. Più nello specifico questo lavoro è strutturato in 7 capitoli così suddivisi: Dopo l’introduzione al lavoro generale, il primo capitolo riguarda una presentazione generale sugli studi sulla gestualità, iniziando dalla definizione di gesto e dai criteri che rendono possibile la distinzione di un gesto da un non-gesto. In questo capitolo, inoltre, viene spiegata l’anatomia dei gesti e l’uso dello spazio da parte dei parlanti. Infine, vengono presentate le principali categorizzazioni che sono state date dai principali studiosi. Lo studio dei gesti, infatti, è una disciplina relativamente giovane, che si è sviluppata soprattutto a partire dalla seconda metà del novecento e per la quale non sono ancora state definite categorie univoche. Il seguente capitolo (capitolo 2), tratta la relazione dei gesti con il parlato. Il rapporto esistente fra parlato e gesti non è del tutto chiaro. Se da una parte, infatti, i gesti e il parlato sono considerati parte di uno stesso sistema linguistico che si sviluppa e interagisce nell’atto comunicativo (McNeill, 1992; Kendon, 2004), dall’altra essi vengono considerati come il risultato di due processi indipendenti (Hostetter, Alibali & Kita, 2007). In generale, comunque, i gesti possono in alcuni casi sostituirsi al parlato, in altri, arricchire il significato semantico e pragmatico di ciò che viene detto, o possono marcarne il ritmo (McNeill, 1992). All’interno di questo capitolo, viene inoltre discusso il rapporto che gesti e parlato hanno sullo sviluppo della prima lingua e sull’apprendimento della seconda lingua, nonché le funzioni che i gesti hanno nella narrazione. Il capitolo 3 si focalizza sul dibattito riguardante le funzioni cognitive e comunicative dei gesti partendo da considerazioni e studi da considerarsi fondativi in questo ambito. Nella prima parte del capitolo vengono presentati i più importanti studi a supporto dell’idea che i gesti siano principalmente legati alle funzioni cognitive e quindi organizzative e lessicali del parlato (v. Beattie & Coughlan, 1999; Hadar & Butterworth, 1997; Rauscher et al., 1996; Kita, 2000, 2010; Krauss et al., 1996). La seconda parte del capitolo illustra gli studi che si concentrano sulla funzione comunicativa e pragmatica che i gesti ricoprono nel parlato (Bavelas et al. 2008; Kendon, 1985, 2004) e, nello specifico, su quale sia il ruolo che i gesti iconici hanno nella comunicazione (v. Cohen & Harrison, 1973; Melinger & Levelt, 2004), Il quarto capitolo è dedicato alla prosodia e alla sua relazione con il sistema gestuale nel parlato. In questo capitolo vengono chiariti i concetti di intonazione e variabilità intonativa sia in L1 che in L2 (v. Hincks, 2004; Mennen et al. 2007; Patterson, 2000). La seconda parte, Experimental analyses, comprende i capitoli 5, 6 e 7 dedicati al lavoro sperimentale. Nel quinto capitolo viene esposto il primo dei due lavori sperimentali. L’ipotesi di partenza è quella che un maggiore sforzo comunicativo da parte del parlante L2 abbia come effetti, da un lato, una maggiore variabilità intonativa rispetto a quella della L1; dall’altra un uso distinto dei gesti rispetto alla condizione L2 nella quale tale sforzo comunicativo è meno consapevole. Il primo dei due effetti, la maggiore variabilità intonativa, sarebbe dovuto al fatto che i soggetti si concentrano maggiormente nella resa comunicativa del parlato e quindi riescono a conferire una variabilità intonativa. In particolare, i parlanti riescono ad avere un’intonazione più simile a quella della L2 (che in questo caso è l’inglese, generalmente percepito come una lingua con maggiore variabilità rispetto all’italiano). Il secondo effetto sarebbe invece dovuto al fatto che i soggetti, per risultare più comunicativi, si concentrerebbero su quei gesti che considerano più importanti a livello comunicativo e percettivo. Il primo esperimento ha coinvolto otto studentesse, frequentanti un corso di Public Speaking all’interno dell’Università di Padova. Alle studentesse è stata fatta leggere la favola di Esopo “Il corvo e la volpe” ed è stato chiesto loro di raccontare la storia due volte: la prima senza ricevere alcuna istruzione specifica e la seconda con la richiesta di cercare di essere il più comunicative possibile. L’analisi del corpus di materiale audiovisivo è stata effettuata: • Tramite un’analisi fonetico-prosodica degli audio (con l’utilizzo del software Praat http://www.fon.hum.uva.nl/praat/) con il quale sono stati misurati: disfluenze, ripetizioni, correzioni, pause piene, pause silenti e pause respiratorie, altezza tonale. Sono state inoltre conteggiate le parole. • Tramite l’analisi gestuale del corpus di video (con l’utilizzo del software Elan, https://tla.mpi.nl/tools/tla-tools/elan/download/) con cui sono stati analizzati i gesti concomitanti al parlato suddividendoli in macro-categorie (rappresentazionali, che descrivono caratteristiche fisico o metaforiche dell’oggetto del discorso; discorsivi, che hanno una relazione ritmica con il parlato e che ne marcano continuità e coesione; emblemi, gesti tipici di una cultura e che sono capiti e condivisi solo da chi fa parte di un determinato gruppo linguistico e/o sociale). I risultati di questo primo esperimento suggeriscono che un maggiore sforzo comunicativo porta ad un aumento della quantità di gesti totali e della percentuale di gesti di tipo iconico-rappresentazionali, oltre che ad una maggiore fluenza, e ad un uso più variato dell’altezza tonale da parte dei soggetti sperimentali. Tale risultato porta alla conclusione che, quando viene richiesto loro di essere comunicativi, i parlanti migliorano la fluenza del parlato, modificano la variazione dell’altezza tonale e implementano un numero maggiore di gesti iconici. Il sesto capitolo è dedicato alla seconda ricerca sperimentale, nella quale le parlanti sono state registrate fuori dal contesto di insegnamento e, nella seconda ripetizione, non è stato chiesto loro di concentrarsi sulla resa comunicativa del proprio racconto. L’esperimento mira ad integrare i risultati raggiunti dall’esperimento con focus sulla resa comunicativa dei soggetti e vuole verificare quali siano le differenze prosodico-gestuali in un contesto in cui alle parlanti (in questo caso sia di L1 che di L2) viene richiesto solamente di ricordare e ripetere il racconto senza dover migliorare la propria performance comunicativa. Nel secondo esperimento sono state coinvolte 10 studentesse di lingue e linguistica di età compresa fra i 22 e i 25 anni, con livello B2 di inglese (CEFR). Alle studentesse è stato fatto vedere un video con un breve cartone animato che illustrava la favola “Il Corvo e la Volpe” di Esopo. Subito dopo aver visto il cartone, le ragazze sono state videoregistrate mentre raccontavano la storia sia in italiano che in inglese. Le stesse studentesse hanno ripetuto l’esperimento dopo una settimana. Per evitare l’effetto di common ground, per il quale si omettono informazioni verbali quando l’interlocutore condivide o è a conoscenza di ciò di cui si sta parlando, il pubblico al quale le studentesse raccontavano la storia è stato cambiato ad ogni ripetizione, sia in italiano che in inglese. Le seguenti analisi sono state effettuate sul materiale audiovisivo: • Analisi fonetico-prosodica del materiale audio con il software di analisi acustica Praat (disfluenze, ripetizioni, correzioni, pause piene, pause silenti e pause respiratorie, altezza tonale). Sono state inoltre conteggiate le parole. • Analisi gestuale del materiale visivo con il software di analisi multimodale Elan. Per poter confrontare i risultati con quelli ottenuti nel primo esperimento, l’annotazione dei gesti co-occorrenti al parlato ha mantenuto la stessa categorizzazione dei gesti in macro-categorie: representational, che comprende tutti i gesti di tipo rappresentazionale, che indicano o rappresentano fisicamente o metaforicamente l’oggetto o l’azione di cui si parla; discursive (ritmico-discorsivi), cioè tutti quei gesti che aiutano il parlante ad organizzare il proprio discorso e/o a marcarne il ritmo. I risultati di questo esperimento hanno mostrato che, nonostante ci sia un effetto di ripetizione, che comporta un miglioramento nella fluenza del parlato (soprattutto in L2, condizione nella quale la differenza fra le due ripetizioni è risultata statisticamente significativa), le parlanti non modificano significativamente i gesti. Il settimo capitolo è dedicato all’integrazione dei risultati e delle conclusioni delle due ricerche e quindi alle considerazioni finali. I risultati dei due esperimenti conducono alla conclusione che all’aumentare dello sforzo comunicativo da parte dei parlanti corrisponde anche una maggiore gestualità, visibile in particolare nell’aumentare della quantità di gesti appartenenti alla macro-categoria rappresentativa (representational). Allo stesso tempo, la riduzione dello sforzo cognitivo nella seconda ripetizione comporta effetti sia sul parlato che sui gesti. Nel parlato, il fatto di essere di fronte ad un compito relativamente più facile (per effetto della ripetizione della storia) porta le studentesse a migliorare la loro fluenza in L2 (si riducono le disfluenze come esitazioni, pause piene, correzioni e ripetizioni). La maggiore facilità nel raccontare la storia, inoltre, permette di aumentare significativamente la variazione dell’altezza tonale nella seconda ripetizione in L2, consentendo alle studentesse di imitare le caratteristiche prosodiche dell’inglese. Dal punto di vista gestuale, invece, non si presentano differenze statisticamente rilevanti fra le ripetizioni, né in italiano, né in inglese. L’unica differenza significativa rilevata è quella dell’uso della categoria rappresentazionale fra la prima ripetizione in Italiano e la prima in inglese. Quando raccontano la storia in inglese, infatti, le studentesse usano un maggior numero di gesti di tipo rappresentazionale, suggerendo così che la rappresentazionalità dei gesti non è solo effetto del maggior intento comunicativo (come si era visto nel primo esperimento) ma è anche effetto del minor sforzo cognitivo. La tesi termina con le considerazioni finali e conclusive sul lavoro svolto e sui risultati ottenuti.

La mia tesi di laurea magistrale ha come tema l’acquisizione delle unità fraseologiche da parte dei bambini in L1, L2 o LS. Al giorno d’oggi siamo immersi in una società cosmopolita, che ci spinge a relazionarci con persone e culture di paesi diversi. È importante, perciò, abituare i nostri bambini a questa realtà fin da piccoli attraverso l’apprendimento delle lingue straniere, cosa che per loro risulta essere un processo molto naturale. Imparare una lingua straniera comporta anche venire a contatto con modi di dire, proverbi, frasi, espressioni di routine, le cosiddette unità fraseologiche. L’elaborato si aprirà con un’introduzione generale alla fraseologia in cui si analizzeranno la definizione di unità fraseologiche, le loro origini in breve, le varie tipologie e le loro proprietà fondamentali. Seguirà un capitolo che illustrerà la competenza fraseologica in generale dal punto di vista del Quadro Comune Europeo di Riferimento e di documenti affini. Successivamente ci sarà una parte dedicata allo stato dell’arte per quel che riguarda l’apprendimento delle unità fraseologiche da parte dei bambini, quindi studi scientifici in merito sia nella L1 che nella L2 e LS. Infine, la tesi si concluderà con una proposta didattica da applicare ai bambini della scuola primaria.

Les rétrotransposons L1 (Long INterspersed Element-1) sont des éléments génétiques mobiles dont l'activité contribue à la dynamique du génome humain par mutagenèse insertionnelle. Les conséquences génétiques et épigénétiques d'une nouvelle insertion, et la capacité d'un L1 à être remobilisé, sont directement liées au site d’intégration dans le génome. Aussi, l’analyse des sites d’intégration des L1s est capitale pour comprendre leur impact fonctionnel - voire pathogène -, en particulier lors de la tumorigenèse ou au cours du vieillissement, et l’évolution de notre génome. Dans ce but, nous avons induit de façon expérimentale la rétrotransposition d'un élément L1 actif plasmidique dans des cellules en culture. Puis, nous avons cartographié les insertions obtenues de novo dans le génome humain grâce à une méthode de séquençage à haut-débit, appelée ATLAS-seq. Finalement, les sites pré-intégratifs identifiés par cette approche ont été analysés en relation avec un grand jeu de données publiques regroupant les caractéristiques structurales, génétiques ou épigénétiques de ces loci. Ces expériences ont révélé que les éléments L1 s’intègrent préférentiellement dans des régions de la chromatine faiblement exprimées et renfermant des activateurs faibles. Nous avons aussi trouvé plusieurs positions chromosomiques qui constituent des points chauds d'intégrations récurrentes. Nos résultats indiquent que la distribution des insertions de L1 de novo n’est pas aléatoire, que ce soit à l’échelle chromosomique ou à plus petite échelle, et ouvrent la porte à l'identification des déterminants moléculaires qui contrôlent la distribution chromosomique des L1s dans notre génome
Retrotransposons are mobile genetic elements that employ an RNA intermediate and a reverse transcription step for their replication. Long INterspersed Elements-1 (LINE-1 or L1) form the only autonomously active retrotransposon family in humans. Although most copies are defective due to the accumulation of mutations, each individual genome contains an average of 100 retrotransposition-competent L1 copies, which contribute to the dynamics of contemporary human genomes. L1 integration sites in the host genome directly determine the genetic consequences of the integration and the fate of the integrated copy. Thus, where L1 integrates in the genome, and whether this process is random, is critical to our understanding of human genome evolution, somatic genome plasticity in cancer and aging, and host-parasite interactions. To characterize L1 insertion sites, rather than studying endogenous L1 which have been subjected to evolutionary selective pressure, we induced de novo L1 retrotransposition by transfecting a plasmid-borne active L1 element into HeLa S3 cells. Then, we mapped de novo insertions in the human genome at nucleotide resolution by a dedicated deep-sequencing approach, named ATLAS-seq. Finally, de novo insertions were examined for their proximity towards a large number of genomic features. We found that L1 preferentially integrates in the lowly-expressed and weak enhancer chromatin segments. We also detected several hotspots of recurrent L1 integration. Our results indicate that the distribution of de novo L1 insertions is non-random both at local and regional scales, and pave the way to identify potential cellular factors involved in the targeting of L1 insertions

Le génome humain est constitué de plus de 45% d'éléments transposables et l'élément LINE-1 (L1), qui représente 17% de la séquence totale, est le seul élément actif connu de notre génome capable de se mobiliser par rétrotransposition. Les protéines produites par L1 peuvent agir en trans et mobiliser ainsi d'autres séquences telles que le SINE Alu, les ARN messagers cellulaires ou encore le snRNA U6. C'est en partie pour ces raisons que l'élément L1 est considéré comme un acteur majeur de la plasticité de notre génome. Au cours de ce travail, nous nous sommes intéressés au recrutement du snRNA U6 par L1 entraînant la formation de rétropseudogènes chimériques. L'objectif principal était de comprendre ce recrutement et d'utiliser les connaissances sur U6 pour mettre en lumière des étapes du mécanisme de rétrotransposition de L1. Les réssultats obtenus indiquent qu'il existe au moins deux mécanismes distincts pour le recrutement d'ARN cellulaires, et que la transcription inverse de ces ARN peut se faire par choix de matrice ou par échange de matrice. Nous avons ensuite mené une analyse comparative du recrutement des snRNA U6 dans les génomes mammifères. Les résulats obtenus reflètent une grande variabilité de la dynamique de rétrotransposition dans les différents génomes étudiés. Dans un deuxième temps, un nouvel outil moléculaire a été développé pour permettre la détection in vitro et ex vivo des molécules produites par l'élément L1 : l'ARN de L1 et les protéines ORF1p et ORF2p. Cet outil a permis d'initier une approche biochimique et une approche cellulaire afin de détecter la formation du complexe ribonucléoprotéique (RNP) de L1. La première approche a permis d'identifier pour la première fois un complexe basal contenant les trois molécules de L1 et à initier la caractérisation des interactions du complexe. La deuxième approche a permis une observation de l'accumulation cytoplasmique de complexes RNP de L1. L'abolition de ce phénotype par des mutations dans le domaine de liaison à l'ARN de la protéine ORF1p a montré son caractère essentiel dans la formation des complexes RNP de L1.

This study contributes a longitudinal naturalistic corpus of a child acquiring Italian as an L1, based on family tapes from age 0;7 to age 3;2. The study aimed to investigate whether it was possible to track the emergence of grammatical categories and structures. It also provides a guide for non experts (e.g. parents) on how to build a similar naturalistic corpus, with particular attention on reliability and consistency. Method Family tapes were analysed and manually transcribed by the researcher. The resulting corpus is consists of 2408 spoken utterances. Overall, 973 utterances, (40.41% of the utterances in the corpus) were produced by the child. The corpus was analysed with Python to verify that all participants were always correctly identified and that no mismatch was accidentally performed. Then, a morphosyntactic analysis was performed on the corpus. This further measure helped at finding word frequencies and determining vocabulary size for the child both to compare it with similar corpora and to verify a gradual but constant growth in the length and complexity of the child’s utterances. Analyses Earlier in the corpus, I noticed an absence of functional words, which were gradually filled with filler words (shwa-fillers). At around 1;5 determiners started to emerge in the child’s production, at first imitating the mother’s speech, then they became more and more independently uttered. This is consistent with most theories discussed in this paper (i.e. Valian 1991, Demuth 2019, Rinaldi et al. 2004, Lorusso et al. 2004, Song et al. 2018, Guasti 1993, Bencini & Valian 2008). Proto-articles, verbs, morphology, and emerging syntax were analysed using the methods in Valian (1991). I examined whether there was evidence for a consistent production increase through time. There was no evidence for consistent increase in the production of correct grammatical forms, however, an overall increase in the length of child-spoken utterances was observed. This lack of evidence is likely due to sparse data in the corpus. Vocabulary increase, on the other hand (Rinaldi et al. 2004, & Song et al. 2018), was detectable and mostly correlated to vocabulary use in the mother’s speech. The distribution of infinitives and clitics was always on target, showing that the distinction between finite and non finite verbs is mastered at an early age (as suggested by Guasti, 1993). The correct identification of shapes through an interactive game with the mother was observed at 1;11. This confirms that the imaginative framework of the child is built at a very early stage, as predicted by Rinaldi et al. (2004). The first unstimulated multi-utterance discourse was uttered at 2;7, when most of the child’s utterances can be described as complete sentences. As Song et al. (2018) observed, speech is a difficult-to-predict behaviour, because it is influenced by a vast number of factors, the predominant one appearing to be mother’s speech. This corpus, despite not being sufficient for a complete analysis, can provide general findings and guidelines to help both researchers and parents to build a consistent and significant corpus in the future.

AbstractImmune checkpoint inhibitors have changed the standard of care for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, only a minority of patients respond, hence the search for predictive biomarkers. Potential predictive biomarkers for immune checkpoint inhibitors discussed in this chapter include (1) Immune checkpoint ligand expression e.g., PD-L1, (2) biomarkers of a T-cell inflamed tumour microenvironment (TME) such as gene expression profiles of activated T cells, (3) biomarkers of tumour neoepitope burden such as tumour mutation burden (TMB) and (4) multidimensional quantitative techniques. At present only PD-L1 expression has been shown to have clinical utility in head and neck cancer. It enriches for populations more likely to respond, but the false positive predictive value remains high. In the pivotal Keynote−048 trial that established a role for pembrolizumab (anti-PD1) monotherapy and pembrolizumab + chemotherapy as treatment options in first-line R/M HNSCC, primary endpoints included overall survival in defined subgroups based on PD-L1 expression. In this trial the combined positive score (CPS) was used which takes into account PD-L1 expression in tumour and immune cells. Based on this trial regulatory approvals for first-line pembrolizumab in R/M HNSCC require assessment of PD-L1 expression using the CPS. Finally we discuss emerging evidence that locoregionally advanced HPV-associated oropharyngeal cancers that have high expression of CD103 positive CD8 T cells have an excellent prognosis and features that suggest increased probability of responding to anti-PD1/PD-L1, raising the possibility of incorporating these immune therapies as part of a de-escalation trial strategy.

AbstractSince the initial reports of activity of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), investigation of the role of immune therapies has been the major focus of clinical trials in R/M HNSCC. Randomised trials initially with nivolumab and later with pembrolizumab established overall survival benefit in patients with R/M HNSCC previously treated with platinum compared to physicians choice of 2nd line therapy, and have led to regulatory approval around the world. More recently the Keynote-048 trial has compared both pembrolizumab monotherapy and pembrolizumab + platinum/5FU to the Extreme regimen of platinum/5FU/cetuximab in the first-line R/M setting. The key findings from this trial are that pembrolizumab monotherapy compared to Extreme improved overall survival in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1, and that pembro/chemotherapy improved OS in CPS ≥ 20, CPS ≥ 1 and the total population. Relative to Extreme there was less toxicity in the monotherapy arm and comparable toxicity in the pembro/chemo arm. Based on this trial use of pembrolizumab as part of first-line treatment for R/M HNSCC is appropriate for the majority of patients, and represents a new standard of care. The focus has now moved to identifying combinations that may be superior to pembrolizumab monotherapy or to chemotherapy + pembrolizumab. Some of the more promising approaches under investigation in HNSCC are discussed in this chapter. In summary, immune therapies are now the cornerstone of management of R/M HNSCC with the approval of pembrolizumab in the first-line R/M setting.

AbstractIn the palliative management of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who are not candidates for a complete resection or full-dose radiotherapy, systemic treatment has seen important advances over the past several decades. In general, there are six major factors impacting on the decision-making process. Four of them belong to a class of continuous functions and include overall health status (from fitness to frailty), disease burden (from high to low), pace of the disease (from fast to slow), and expression of programmed-death ligand 1 (PD-L1, from high to low). In addition, there are two categorical variables including disease site (e.g., locoregional recurrence versus metastatic) and platinum-sensitivity or resistance depending on disease-free interval after previous platinum-based therapy with a usual cut-off of 6 months. Taking into account these six factors and local drug policies, healthcare professionals opt either for 1) chemotherapy with or without cetuximab or 2) immunotherapy with or without chemotherapy. In platinum-sensitive cases, level I evidence based on data from the EXTREME and Keynote-048 randomized trials supports the use of the following three regimens. Biochemotherapy combining platinum, 5-fluorouracil, and cetuximab (the so-called EXTREME regimen) is suitable for fit patients with low PD-L1 expression measured as combined positive score (CPS). Higher CPS is predictive for improved overall survival when replacing cetuximab with the immune checkpoint inhibitor pembrolizumab, an anti-PD-1 antibody (immunochemotherapy regimen). Further, Keynote-048 demonstrated activity of single-agent pembrolizumab in patients with high CPS values. The latter (third) treatment retained its efficacy in the elderly, suggesting possible advantage in less fit patients who otherwise receive best supportive care only or single-agent cytotoxic chemotherapy with dubious impact on survival. In selected patients, the TPEx regimen consisting of cisplatin, docetaxel, and cetuximab represents an alternative to EXTREME. Treatment choice can also be influenced by disease extension (site). Compared with disseminated cancer cases, presence of locoregional recurrence without distant metastases may have a negative predictive value for immune checkpoint inhibitors, while favouring biochemotherapy. If the tumour is deemed platinum-resistant, the only evidence-based systemic approach is monotherapy with either pembrolizumab or nivolumab, another anti-PD-1 antibody. Alternatively, being especially pertinent to resource-limited countries, a taxane with or without cetuximab can be prioritized. Obviously, the list of different treatment schedules is longer, but the level of supporting evidence is proportionally lower. One of modern approaches to multidisciplinary management of SCCHN patients is treatment sequencing. It should be understood as a deliberate process of treatment planning typically starting in the locally advanced setting and reaching beyond several treatment failures. This has been enabled by a growing portfolio of effective anticancer modalities complemented by progress in supportive care. Finally, all therapeutic interventions impact somehow on quality of life, either in a positive or negative way, and the choice of anticancer agents should therefore not be reduced to a simple estimate of survival benefit but should contain an adequate appraisal and understanding of individual patient’s situation comprising emotional and spiritual dimensions, cultural and financial aspects, and environmental, social, and educational contexts.

Objective: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have emerged as the first line for patients with mTNBC whose tumors are PD-L1 positive. However, given the paucity of data in Brazilian populations, the objective of this study was to evaluate the prevalence of PD-L1 positive mTNBC in a single Brazilian center and its association with tumor-infiltrating lymphocytes (TIL). Methods: We assembled a retrospective cohort of all patients with metastatic breast cancer who have been tested for PD-L1 biomarker from January 2018 to December 2020. Patient’s clinical information, including use of ICI, and PD-L1 status, was obtained from the electronic medical record’s analysis, and the TIL slide’s material was reviewed by a single pathologist. TIL were assessed according to the international consensus and were classified as low, intermediate, and high TIL, respectively, if they present with 60%. Survival data (overall survival and progression-free survival) for TNBC patients who have been treated with immunotherapy are presented. Results: Among the 46 female patients tested for PD-L1 in our institution, 25 (54.4%) presented with mTNBC. Among this group (median age of 46 years), the majority was diagnosed between 2016 and 2020 (56%), in stages I or II (56%), and had invasive ductal carcinomas (96%). Most patients (23; 92%) underwent the SP-142 Ventana test, and the prevalence of positive (PD-L1 ≥ 1%) patients was 40%. Samples from primary tumor were more likely to be PD-L1 positive (9/17; 53%) compared with samples from metastatic sites (1/8; 12.5%) tumors. A total of 19 patients had TIL assessment. Most cases presented with low TIL (n=14; 73.7%), followed by intermediate TIL (n=5; 26.3%), and no cases of high TIL. Patients with PD-L1 negative tumors were more likely to present tumors with low TIL (9/11; 81.8%) versus those with PD-L1 positive tumors (5/8; 62.5%). A total of 13 patients received ICI plus chemotherapy. For this subset of patients, the median age was 47 years, 69.3% (n=9) had PD-L1 positive tumors, and most of them (n=12) received atezolizumab plus nab-paclitaxel. Only one patient received ICI as the first line. The median PFS was 2.36 months (2.4 months for PD-L1+ and 2.01 months PD-L1−). Two patients received the combination of ICI plus chemotherapy for >6 months. Disease progression was the main reason (64%) for ICI interruption. Only one patient stopped therapy for toxicity (neuropathy). Conclusion: To the best of our knowledge, this is the first “real-world” Brazilian study evaluating the prevalence of PD-L1 positive mTNBC and its association with TIL. The prevalence of PD-L1 in mTNBC is consistent with scientific literature, and physicians should prioritize performing the test in samples from primary tumors

Introdução: Em junho de 2019 foi aprovado pela ANVISA a utilização do atezolizumabe como inibidor de anti- PDL1 , para o tratamento de câncer de pulmão em estágio III tendo a associação com quimioterapia baseado em platina. O atezolizumabe, conhecido também como Tecentriq® é um anticorpo monoclonal de imunoglobulina G1 humanizado com domínio Fc, onde se liga diretamente ao PD-1 que possibilita um bloqueio duplo dos receptores PD-1 e B7.1, ocasionando uma inibição mediada pela via PD-L1/ PD-1 da resposta imune, envolvendo uma reativação de resposta imune antitumoral sem induzir citotoxicidade celular dependente de anticorpo. Assim possibilitando que os sinais inibitórios mediados por PD-L2/ PD-L1 continuem. Objetivos: Descrever a relevância do Atezolizumabe como imunoterápico no câncer de pulmão, para o tratamento de pacientes adultos com câncer de pulmão de não-pequenas células (CPNPC) localmente avançado ou metastático após quimioterapia prévia.Material e Métodos: O trabalho trata-se de uma revisão bibliográfica, com levantamento de informações e discernimento acerca de artigos que abordem o tema, apontando uma nova forma benéfica terapêutica, produzido pela engenharia genética com a utilização de anticorpo humanizado. Resultados: A partir dos artigos estudados pode-se constatar que o tratamento com o Atezolizumabe tem funcionalidade ao adulto que apresenta CPNPC localmente avançado ou metastático posteriormente a quimioterapia prévia e em pacientes com mutações ativadoras EGRF ou mutações ALK positivado após recebimento de terapia alvo promovendo benefícios em relação a sobrevida da população desses estudos. Conclusão: De acordo com a análise dos estudos referente a temática, a imunoterapia associada a quimioterapia trás consigo um aumento benéfico na sobrevida de pacientes que apresentam CPNPC do que só a quimioterapia em si.

Introdução: Os dípteros muscóides apresentam grande importância em medicinaveterinária e saúde pública por serem carreadores de patógenos e causadores de miíases. O uso de inseticidas químicos tem sido utilizado atualmente como principal método de controle dessas moscas, são altamente eficazes, mas podem causar danos ao meio ambiente, aos animais domésticos e aos seres humanos. Uma forma alternativa a este tipo de controle são os bioinseticidas, produzidos a partir de metabólitos secundários de plantas, os quais são rapidamente degradados no meio, minimizando riscos à saúde. Objetivo: Este estudo teve como objetivo avaliar o efeito de extratos etanólicos de folhas e de sementes de Moringa oleifera sobre o desenvolvimento pós-embrionário de C. putoria. Material e métodos: Para os testes foram utilizadas larvas recém eclodidas (L1) tratadas com diferentes concentrações de extratos etanólicos de sementes e de folhas de M. oleifera (5 mg/L, 10 mg/L, 25 mg/L, 50 mg/L, 75 mg/L e 100 mg/L). Foram utilizadas 3 réplicas (30 (L1)) para cada concentração, um grupo controle (sem substância) e um grupo controle com DMSO. As larvas recém eclodidas foram tratadas topicamente com a solução com o auxílio da pipeta, sendo usado 1μL/neolarva. Os parâmetros analisados foram o peso das larvas maduras (L3), duração do período larval, pupal e da fase de neolarva a adulto, assim como a viabilidade dos estágios de desenvolvimento, e a razão sexual. Resultados: Os resultados mostraram que os extratos de folhas e de sementes de M. oleifera causaram efeitos semelhantes em todas as concentrações testadas, atrasando o desenvolvimento pós-embrionário e reduzindo o peso larval. Quanto a mortalidade, no período de neolarva a adulto as concentrações de 50, 75 e 100 mg/L dos extratos de folhas e de sementes de M. oleifera se mostraram eficazes, matando acima de 20%. O controle sem/com DMSO não apresentaram mortes em nenhum dos estágios pós-embrionários. Conclusão: Os extratos de folhas e de sementes de M. oleifera se mostraram uma alternativa viável para o controle da mosca da espécie C. putoria.

3D line skeletons are simplistic representations of a shape’s topology which are used for a wide variety of geometry-processing tasks, including shape recognition, retrieval, and reconstruction. Numerous methods have been proposed to generate a skeleton from a given 3D shape. While mesh-based methods can exploit existing knowledge about the shape’s topology and orientation, point-based techniques often resort to precomputed per- point normals to ensure robustness. In contrast, previously proposed techniques for unprocessed point clouds either exhibit inferior robustness or require expensive operations, which in turn increases computation time. In this paper, we present a new and highly efficient skeletonization approach for raw point cloud data, which produces overall competitive results compared to previous work, while exhibiting much lower computation times. Our algo- rithm performs robustly in the face of noisy and fragmented inputs, as they are usually obtained from real-world 3D scans. We achieve this by first transferring the input point cloud into a Gaussian mixture model (GMM), obtaining a more compact representation of the surface. Our method then iteratively projects a small subset of the points into local L1-medians, yielding a rough outline of the shape’s skeleton. Finally, we present a new branch detection technique to obtain a coherent line skeleton from those projected points. We demonstrate the capabilities of our proposed method by extracting the line skeletons of a diverse selection of input shapes and evaluating their visual appearance as well as the efficiency compared to alternative state-of-the-art methods.

Abstract Does the hysteresis effect remain in each cell after division? In the present study, the cell activity has been investigated after division under a shear stress field. To apply the constant shear stress field on cells, a Couette type flow device has been manufactured: between parallel walls (a lower stationary culture disk, and an upper rotating disk) with a constant gap. The wall shear stress was controlled by the rotating speed of the upper disk. Four types of cells were used in the test: C2C12 (mouse myoblast cell line), HUVEC (Human Umbilical Vein Endothelial Cells), 3T3-L1 (mouse fat precursor cells), and L929 (mouse fibroblast connective tissue). After cultivation without flow for 24 hours for adhesion of cells on the lower plate, the shear stress of 1 Pa was continuously applied on cells for 7 days at 310 K. The behavior (alignment and deformation) of each cell was traced at the time lapse image observed by an inverted phase contrast microscope placed in an incubator. The experimental results show the following behavior of each type of cell: C2C12 tends to return to the same direction as that of before division. Deformed 3T3-L1 tends to tilt to the flow direction.

Repetitive control system is a servo system that achieves zero steady-state tracking error for any periodic desired outputs and any periodic disturbance inputs with a known period. This paper deals with a repetitive control problem for the case where the plant has a norm-bounded uncertainty and the period of periodic disturbances is unknown but is within known lower and upper bounds. A new robust repetitive controller is proposed not only to guarantee the robust stability against the uncertainty but also to estimate the unknown period and to reject any periodic disturbances with the period. It is shown that the design problem is reduced to a simple and feasible l1 norm minimization problem. The controller can be obtained easily by solving a simple linear programming problem. Simulation results show the effectiveness of the proposed controller for rejection of periodic disturbances with uncertain periods.

Background Australia is a multi-cultural society with increasing rates of people from culturally and linguistically diverse (CALD) backgrounds. On average, CALD groups have higher rates of tobacco use, lower participation in cancer screening programs, and poorer health outcomes than the general Australian population. Lower cancer screening and smoking cessation rates are due to differing cultural norms, health-related attitudes, and beliefs, and language barriers. Interventions can help address these potential barriers and increase tobacco cessation and cancer screening rates among CALD groups. Cancer Council NSW (CCNSW) aims to reduce the impact of cancer and improve cancer outcomes for priority populations including CALD communities. In line with this objective, CCNSW commissioned this rapid review of interventions implemented in Australia and comparable countries. Review questions This review aimed to address the following specific questions: Question 1 (Q1): What smoking cessation interventions have been proven effective in reducing or preventing smoking among culturally and linguistically diverse communities? Question 2 (Q2): What screening interventions have proven effective in increasing participation in population cancer screening programs among culturally and linguistically diverse populations? This review focused on Chinese-, Vietnamese- and Arabic-speaking people as they are the largest CALD groups in Australia and have high rates of tobacco use and poor screening adherence in NSW. Summary of methods An extensive search of peer-reviewed and grey literature published between January 2013-March 2022 identified 19 eligible studies for inclusion in the Q1 review and 49 studies for the Q2 review. The National Health and Medical Research Council (NHMRC) Levels of Evidence and Joanna Briggs Institute’s (JBI) Critical Appraisal Tools were used to assess the robustness and quality of the included studies, respectively. Key findings Findings are reported by components of an intervention overall and for each CALD group. By understanding the effectiveness of individual components, results will demonstrate key building blocks of an effective intervention. Question 1: What smoking cessation interventions have been proven effective in reducing or preventing smoking among culturally and linguistically diverse communities? Thirteen of the 19 studies were Level IV (L4) evidence, four were Level III (L3), one was Level II (L2), none were L1 (highest level of evidence) and one study’s evidence level was unable to be determined. The quality of included studies varied. Fifteen tobacco cessation intervention components were included, with most interventions involving at least three components (range 2-6). Written information (14 studies), and education sessions (10 studies) were the most common components included in an intervention. Eight of the 15 intervention components explored had promising evidence for use with Chinese-speaking participants (written information, education sessions, visual information, counselling, involving a family member or friend, nicotine replacement therapy, branded merchandise, and mobile messaging). Another two components (media campaign and telephone follow-up) had evidence aggregated across CALD groups (i.e., results for Chinese-speaking participants were combined with other CALD group(s)). No intervention component was deemed of sufficient evidence for use with Vietnamese-speaking participants and four intervention components had aggregated evidence (written information, education sessions, counselling, nicotine replacement therapy). Counselling was the only intervention component to have promising evidence for use with Arabic-speaking participants and one had mixed evidence (written information). Question 2: What screening interventions have proven effective in increasing participation in population cancer screening programs among culturally and linguistically diverse populations? Two of the 49 studies were Level I (L1) evidence, 13 L2, seven L3, 25 L4 and two studies’ level of evidence was unable to be determined. Eighteen intervention components were assessed with most interventions involving 3-4 components (range 1-6). Education sessions (32 studies), written information (23 studies) and patient navigation (10 studies) were the most common components. Seven of the 18 cancer screening intervention components had promising evidence to support their use with Vietnamese-speaking participants (education sessions, written information, patient navigation, visual information, peer/community health worker, counselling, and peer experience). The component, opportunity to be screened (e.g. mailed or handed a bowel screening test), had aggregated evidence regarding its use with Vietnamese-speaking participants. Seven intervention components (education session, written information, visual information, peer/community health worker, opportunity to be screened, counselling, and branded merchandise) also had promising evidence to support their use with Chinese-speaking participants whilst two components had mixed (patient navigation) or aggregated (media campaign) evidence. One intervention component for use with Arabic-speaking participants had promising evidence to support its use (opportunity to be screened) and eight intervention components had mixed or aggregated support (education sessions, written information, patient navigation, visual information, peer/community health worker, peer experience, media campaign, and anatomical models). Gaps in the evidence There were four noteworthy gaps in the evidence: 1. No systematic review was captured for Q1, and only two studies were randomised controlled trials. Much of the evidence is therefore based on lower level study designs, with risk of bias. 2. Many studies provided inadequate detail regarding their intervention design which impacts both the quality appraisal and how mixed finding results can be interpreted. 3. Several intervention components were found to have supportive evidence available only at the aggregate level. Further research is warranted to determine the interventions effectiveness with the individual CALD participant group only. 4. The evidence regarding the effectiveness of certain intervention components were either unknown (no studies) or insufficient (only one study) across CALD groups. This was the predominately the case for Arabic-speaking participants for both Q1 and Q2, and for Vietnamese-speaking participants for Q1. Further research is therefore warranted. Applicability Most of the intervention components included in this review are applicable for use in the Australian context, and NSW specifically. However, intervention components assessed as having insufficient, mixed, or no evidence require further research. Cancer screening and tobacco cessation interventions targeting Chinese-speaking participants were more common and therefore showed more evidence of effectiveness for the intervention components explored. There was support for cancer screening intervention components targeting Vietnamese-speaking participants but not for tobacco cessation interventions. There were few interventions implemented for Arabic-speaking participants that addressed tobacco cessation and screening adherence. Much of the evidence for Vietnamese and Arabic-speaking participants was further limited by studies co-recruiting multiple CALD groups and reporting aggregate results. Conclusion There is sound evidence for use of a range of intervention components to address tobacco cessation and cancer screening adherence among Chinese-speaking populations, and cancer screening adherence among Vietnamese-speaking populations. Evidence is lacking regarding the effectiveness of tobacco cessation interventions with Vietnamese- and Arabic-speaking participants, and cancer screening interventions for Arabic-speaking participants. More research is required to determine whether components considered effective for use in one CALD group are applicable to other CALD populations.