Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Psychol Res ; 84(2): 514-527, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30047022

RESUMO

When two dialogue partners need to refer to something, they jointly negotiate which referring expression should be used. If needed, the chosen referring expression is then reused throughout the interaction, which potentially has a direct, positive impact on subsequent communication. The purpose of this study was to determine if the way in which the partners view, or conceptualise, the referent under discussion, affects referring expression negotiation and subsequent communication. A matching task was preceded by an individual task during which participants were required to describe their conceptualisations of abstract tangram pictures. The results revealed that participants found it more difficult to converge on single referring expression during the matching task when they initially held different conceptualisations of the pictures. This had a negative impact on the remainder of the task. These findings are discussed in light of the shared versus mutual knowledge distinction, highlighting how the former directly contributes to the formation of the latter.


Assuntos
Comunicação , Formação de Conceito , Comportamento Cooperativo , Feminino , Humanos , Masculino , Desempenho Psicomotor , Adulto Jovem
2.
Int J Cancer ; 145(11): 3163-3172, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31107542

RESUMO

We examined whether 66 germline single-nucleotide polymorphisms (SNPs) in 10 candidate genes would predict clinical outcome in 316 patients with resectable locally advanced rectal cancer (LARC) enrolled in the ACCORD-12 phase III trial who were randomly treated with preoperative radiotherapy plus capecitabine (CAP45; n = 155) or dose-intensified radiotherapy plus capecitabine and oxaliplatin (CAPOX50; n = 161). The primary endpoint was tumor response according to the Dworak score. Multivariate logistic regression models adjusted on treatment arm and T stage determined the SNPs prognostic and predictive values for tumor response. In univariate analysis, five SNPs in ERCC2, XPA, MTHFR and ERCC1 were associated with the Dworak score in the CAPOX50 arm. In the overall population, interaction with treatment arm was significant for ERCC2 rs1799787 (pinteraction = 0.05) and XPA rs3176683 (pinteraction = 0.008), suggesting a predictive effect for response to oxaliplatin-based chemoradiotherapy (CRT). All but XPA rs3176683 had a prognostic effect on tumor response. In a multivariate model, interaction remained significant for XPA rs3176683 ([OR 7.33, 95% CI 1.40-38.23], pinteraction = 0.018) and the prognostic effect significant for ERCC2 rs1799787 ([OR 0.55, 95%CI 0.32-0.93], p = 0.027) and ERCC1 rs10412761 ([OR 0.57, 95%CI 0.34-0.98], p = 0.042). Patients with the T/G haplotype of rs1799787 and rs10412761 had a 60% decrease in odds of response (p < 0.001). None of the five SNPs were associated with toxicity, overall and disease-free survival. These data suggest that genetic variation in DNA repair genes influences response to preoperative CRT in LARC and identify patients who benefit from the addition of oxaliplatin to CRT.


Assuntos
Capecitabina/uso terapêutico , Quimiorradioterapia/métodos , Oxaliplatina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Neoplasias Retais/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Reparo do DNA , Feminino , Redes Reguladoras de Genes , Mutação em Linhagem Germinativa , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/genética , Análise de Sobrevida , Resultado do Tratamento
3.
Mem Cognit ; 45(1): 151-167, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27531139

RESUMO

According to the documents model framework (Britt, Perfetti, Sandak, & Rouet, 1999), readers' detection of contradictions within texts increases their integration of source-content links (i.e., who says what). This study examines whether conflict may also strengthen the relationship between the respective sources. In two experiments, participants read brief news reports containing two critical statements attributed to different sources. In half of the reports, the statements were consistent with each other, whereas in the other half they were discrepant. Participants were tested for source memory and source integration in an immediate item-recognition task (Experiment 1) and a cued recall task (Experiments 1 and 2). In both experiments, discrepancies increased readers' memory for sources. We found that discrepant sources enhanced retrieval of the other source compared to consistent sources (using a delayed recall measure; Experiments 1 and 2). However, discrepant sources failed to prime the other source as evidenced in an online recognition measure (Experiment 1). We argue that discrepancies promoted the construction of links between sources, but that integration did not take place during reading.


Assuntos
Conflito Psicológico , Sinais (Psicologia) , Memória de Curto Prazo/fisiologia , Rememoração Mental/fisiologia , Reconhecimento Psicológico/fisiologia , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
4.
Dev Sci ; 19(6): 1087-1094, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26690306

RESUMO

The association of colour with emotion constitutes a growing field of research, as it can affect how humans process their environment. Although there has been increasing interest in the association of red with negative valence in adults, little is known about how it develops. We therefore tested the red-negative association in children for the first time. Children aged 5-10 years performed a face categorization task in the form of a card-sorting task. They had to judge whether ambiguous faces shown against three different colour backgrounds (red, grey, green) seemed to 'feel good' or 'feel bad'. Results of logistic mixed models showed that - as previously demonstrated in adults - children across the age range provided significantly more 'feel bad' responses when the faces were given a red background. This finding is discussed in relation to colour-emotion association theories.


Assuntos
Cor , Emoções/fisiologia , Associação , Criança , Pré-Escolar , Face , Feminino , Humanos , Masculino
5.
Clin Cancer Res ; 30(18): 4143-4154, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-38630555

RESUMO

PURPOSE: Osimertinib is an EGFR tyrosine kinase inhibitor indicated for the treatment of EGFR-mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line-treated patients with EGFRm advanced non-small cell lung cancer (NSCLC). Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. EXPERIMENTAL DESIGN: ctDNA profiling analysis of on-progression plasma samples from patients treated with osimertinib in both first- (phase III, FLAURA trial) and second-line trials (phase III, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR-engineered NSCLC cell lines and patient-derived xenograft (PDX) models supports a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance. RESULTS: These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be resensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alterations, and in these double-mutant models, capivasertib and osimertinib combination elicits an improved antitumor effect versus osimertinib alone. CONCLUSIONS: Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC who have a suboptimal response or develop resistance to osimertinib through PIK3CA/AKT/PTEN alterations. See related commentary by Vokes et al., p. 3968.


Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Classe I de Fosfatidilinositol 3-Quinases , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Mutação , PTEN Fosfo-Hidrolase , Proteínas Proto-Oncogênicas c-akt , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , PTEN Fosfo-Hidrolase/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Compostos de Anilina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/administração & dosagem , Indóis , Pirróis
6.
Clin Cancer Res ; 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39226398

RESUMO

PURPOSE: Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies. EXPERIMENTAL DESIGN: We analyzed sequential ctDNA, +/- WES or targeted NGS on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenografts (PDX) models were used for functional studies. RESULTS: Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g. pemigatinib, erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated; after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefitted from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on PDX, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y. CONCLUSIONS: At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and inter-patient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly-oriented treatment strategies across FGFR2-driven tumors.

7.
Eur Urol Oncol ; 7(3): 527-536, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38433714

RESUMO

BACKGROUND: Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models. OBJECTIVE: To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy. DESIGN, SETTING, AND PARTICIPANTS: NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test. RESULTS AND LIMITATIONS: Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity. CONCLUSIONS: Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms. PATIENT SUMMARY: In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Animais , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Modelos Animais de Doenças
8.
Cancer Discov ; : OF1-OF20, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39269178

RESUMO

Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion-positive non-small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested. In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs. In vivo, it induces regression across 12 tumor models, including intracranial and patient-derived xenografts. NVL-655 inhibits ALK over TRK with 22-fold to >874-fold selectivity. These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion-positive non-small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.

9.
Ergonomics ; 56(12): 1863-76, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24168472

RESUMO

The visual interfaces of virtual environments such as video games often show scenes where objects are superimposed on a moving background. Three experiments were designed to better understand the impact of the complexity and/or overall motion of two types of visual backgrounds often used in video games on the detection and use of superimposed, stationary items. The impact of background complexity and motion was assessed during two typical video game tasks: a relatively complex visual search task and a classic, less demanding shooting task. Background motion impaired participants' performance only when they performed the shooting game task, and only when the simplest of the two backgrounds was used. In contrast, and independently of background motion, performance on both tasks was impaired when the complexity of the background increased. Eye movement recordings demonstrated that most of the findings reflected the impact of low-level features of the two backgrounds on gaze control.


Assuntos
Movimento (Física) , Nistagmo Optocinético/fisiologia , Análise e Desempenho de Tarefas , Jogos de Vídeo , Adolescente , Feminino , Humanos , Masculino , Reconhecimento Visual de Modelos , Mascaramento Perceptivo , Estimulação Luminosa , Adulto Jovem
10.
Sci Rep ; 13(1): 174, 2023 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-36599964

RESUMO

Studies of the impact of face masks on emotional facial expression recognition are sparse in children. Moreover, to our knowledge no study has so far considered mask color (in adults and in children), even though this esthetic property is thought to have an impact on information processing. In order to explore these issues, the present study looked at whether first- and fifth-graders and young adults were influenced by the absence or presence (and color: pink, green, red, black, or white) of a face mask when asked to judge emotional facial expressions of fear, anger, sadness, or neutrality. Analysis of results suggested that the presence of a mask did affect the recognition of sad or fearful faces but did not influence significantly the perception of angry and neutral faces. Mask color slightly modulated the recognition of facial emotional expressions, without a systematic pattern that would allow a clear conclusion to be drawn. Moreover, none of these findings varied according to age group. The contribution of different facial areas to efficient emotion recognition is discussed with reference to methodological and theoretical considerations, and in the light of recent studies.


Assuntos
Reconhecimento Facial , Adulto Jovem , Criança , Humanos , Estudos Transversais , Emoções , Ira , Medo , Expressão Facial
11.
Cancer Discov ; 13(9): 1998-2011, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37377403

RESUMO

Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with FGFR-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 4 TSC1/2, n = 4 PIK3CA, n = 1 TSC1 and PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation. SIGNIFICANCE: In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K-mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR , Classe I de Fosfatidilinositol 3-Quinases , Fosfatidilinositol 3-Quinases
12.
Clin Cancer Res ; 29(21): 4504-4517, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37364000

RESUMO

PURPOSE: The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. EXPERIMENTAL DESIGN: In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests. RESULTS: WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples. CONCLUSIONS: Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs' resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation. See related commentary by Slovin, p. 4323.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Proteínas Hedgehog , Estudos Prospectivos , Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/genética , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Genômica , Nitrilas
13.
Q J Exp Psychol (Hove) ; 75(7): 1330-1342, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34623189

RESUMO

People's memory of what was said and who said what during dialogue plays a central role in mutual comprehension and subsequent adaptation. This article outlines that well-established effects in conversational memory such as the self-production and the emotional effects actually depend on the nature of the interaction. We specifically focus on the impact of the collaborative nature of the interaction, comparing participants' conversational memory in non-collaborative and collaborative interactive settings involving interactions between two people (i.e., dialogue). The findings reveal that the amplitude of these conversational memory effects depends on the collaborative vs. non-collaborative nature of the interaction. The effects are attenuated when people have the opportunity to collaborate because information that remained non-salient in the non-collaborative condition (neutral and partner-produced words) became salient in the collaborative condition to a level similar to otherwise salient information (emotional and self-produced words). We highlight the importance of these findings in the study of dialogue and conversational memory.


Assuntos
Comunicação , Emoções , Humanos
14.
Ergonomics ; 53(1): 43-55, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20069480

RESUMO

The aim of the study was to determine the influence of textual feedback on the content and outcome of spoken interaction with a natural language dialogue system. More specifically, the assumption that textual feedback could disrupt spoken interaction was tested in a human-computer dialogue situation. In total, 48 adult participants, familiar with the system, had to find restaurants based on simple or difficult scenarios using a real natural language service system in a speech-only (phone), speech plus textual dialogue history (multimodal) or text-only (web) modality. The linguistic contents of the dialogues differed as a function of modality, but were similar whether the textual feedback was included in the spoken condition or not. These results add to burgeoning research efforts on multimodal feedback, in suggesting that textual feedback may have little or no detrimental effect on information searching with a real system. STATEMENT OF RELEVANCE: The results suggest that adding textual feedback to interfaces for human-computer dialogue could enhance spoken interaction rather than create interference. The literature currently suggests that adding textual feedback to tasks that depend on the visual sense benefits human-computer interaction. The addition of textual output when the spoken modality is heavily taxed by the task was investigated.


Assuntos
Processamento de Linguagem Natural , Interface Usuário-Computador , Comportamento Verbal , Adulto , Comunicação , Auxiliares de Comunicação para Pessoas com Deficiência , Estudos de Viabilidade , Feminino , Humanos , Internet , Masculino , Leitura , Adulto Jovem
15.
NPJ Precis Oncol ; 4: 27, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32964129

RESUMO

Unravelling the biological processes driving tumour resistance is necessary to support the development of innovative treatment strategies. We report the design and feasibility of the MATCH-R prospective trial led by Gustave Roussy with the primary objective of characterizing the molecular mechanisms of resistance to cancer treatments. The primary clinical endpoints consist of analyzing the type and frequency of molecular alterations in resistant tumours and compare these to samples prior to treatment. Patients experiencing disease progression after an initial partial response or stable disease for at least 24 weeks underwent a tumour biopsy guided by CT or ultrasound. Molecular profiling of tumours was performed using whole exome sequencing, RNA sequencing and panel sequencing. At data cut-off for feasibility analysis, out of 333 inclusions, tumour biopsies were obtained in 303 cases (91%). From these biopsies, 278 (83%) had sufficient quality for analysis by high-throughput next generation sequencing (NGS). All 278 samples underwent targeted NGS, 215 (70.9%) RNA sequencing and 222 (73.2%) whole exome sequencing. In total, 163 tumours were implanted in NOD scid gamma (NSG) or nude mice and 54 patient-derived xenograft (PDX) models were established, with a success rate of 33%. Adverse events secondary to invasive tumour sampling occurred in 24 patients (7.6%). Study recruitment is still ongoing. Systematic molecular profiling of tumours and the development of patient-derived models of acquired resistance to targeted agents and immunotherapy is feasible and can drive the selection of the next therapeutic strategy.

16.
Clin Cancer Res ; 26(1): 242-255, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31585938

RESUMO

PURPOSE: Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting. EXPERIMENTAL DESIGN: Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance. RESULTS: Diverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial-mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors. CONCLUSIONS: This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Lactamas Macrocíclicas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Aminopiridinas , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Rearranjo Gênico , Humanos , Lactamas , Lactamas Macrocíclicas/uso terapêutico , Estudos Longitudinais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Neurofibromina 2/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cognition ; 180: 52-58, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29981968

RESUMO

The joint impact of emotion and production on conversational memory was examined in two experiments where pairs of participants took turns producing verbal information. They were instructed to produce out loud sentences based on either neutral or emotional (Experiment 1: negative; Experiment 2: positive) words. Each participant was then asked to recall as many words as possible (content memory) and to indicate who had produced each word (reality monitoring). The analyses showed that both self-production and emotion boost content memory, although emotion also impairs reality monitoring. This study sheds light on how both factors (emotion and production) may constrain language interaction memory through information saliency.


Assuntos
Emoções/fisiologia , Rememoração Mental/fisiologia , Estimulação Luminosa/métodos , Reconhecimento Psicológico/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Memória/fisiologia , Adulto Jovem
18.
J Exp Psychol Appl ; 24(4): 476-489, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30346193

RESUMO

This study examined the effect of the number of citations attributed to documents on third year psychology students' selection of bibliographical references. Our main assumption was that students would take high numbers of citations as accessible relevance cues and use them heuristically to facilitate decision making, potentially bypassing deeper relevance assessment based on semantic processing. Experiment 1 presented the students with a reference selection task while manipulating the number of citations attributed to references, and found that the number of citations had a strong impact on reference selection. Moreover, the effect was independent from topic familiarity and even from students' prior knowledge of what the number of citations meant. Experiment 2 used eye-tracking data to show that this "big number" effect was contingent upon the participants fixating the numbers of citations attributed to documents. Experiment 3 manipulated the semantic relevance of references to the search topic, and demonstrated that the less relevant references were 3 times more likely to be selected when they came with a high number of citations. Overall, the study shows that the number of citations significantly influences students' selections, competing with the semantic relevance of references. Implications for the teaching of online search skills are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Assuntos
Bibliografias como Assunto , Tomada de Decisões , Heurística , Estudantes , Adolescente , Adulto , Feminino , Humanos , Conhecimento , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
J Clin Invest ; 128(4): 1671-1687, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29447131

RESUMO

Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Reparo do DNA , Neoplasias Pulmonares/metabolismo , NAD/biossíntese , Neoplasias Experimentais/metabolismo , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Citocinas/genética , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Nus , NAD/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo
20.
Nat Cell Biol ; 20(3): 296-306, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29403038

RESUMO

Metastases account for 90% of cancer-related deaths; thus, it is vital to understand the biology of tumour dissemination. Here, we collected and monitored >50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastatic spread to the peritoneum. This reveals an unpredicted mode of dissemination. Large clusters of cancer epithelial cells displaying a robust outward apical pole, which we termed tumour spheres with inverted polarity (TSIPs), were observed throughout the process of dissemination. TSIPs form and propagate through the collective apical budding of hypermethylated CRCs downstream of canonical and non-canonical transforming growth factor-ß signalling. TSIPs maintain their apical-out topology and use actomyosin contractility to collectively invade three-dimensional extracellular matrices. TSIPs invade paired patient peritoneum explants, initiate metastases in mice xenograft models and correlate with adverse patient prognosis. Thus, despite their epithelial architecture and inverted topology TSIPs seem to drive the metastatic spread of hypermethylated CRCs.


Assuntos
Biomarcadores Tumorais/genética , Movimento Celular , Polaridade Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Metilação de DNA , Células Epiteliais/patologia , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/secundário , Animais , Biomarcadores Tumorais/metabolismo , Células CACO-2 , Neoplasias Colorretais/metabolismo , Células Epiteliais/metabolismo , Predisposição Genética para Doença , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Neoplasias Peritoneais/metabolismo , Fenótipo , Estudos Prospectivos , Transdução de Sinais , Fatores de Tempo , Fator de Crescimento Transformador beta/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA