CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing

BACKGROUND: Chimeric antigen receptor (CAR)-based T cell therapy is in early clinical trials to target the neuroectodermal tumor, neuroblastoma. No preclinical or clinical efficacy data are available for retinoblastoma to date. Whereas unilateral intraocular retinoblastoma is cured by enucleation of the eye, infiltration of the optic nerve indicates potential diffuse scattering and tumor spread leading to a major therapeutic challenge. CAR-T cell therapy could improve the currently limited therapeutic strategies for metastasized retinoblastoma by simultaneously killing both primary tumor and metastasizing malignant cells and by reducing chemotherapy-related late effects. METHODS: CD171 and GD2 expression was flow cytometrically analyzed in 11 retinoblastoma cell lines. CD171 expression and T cell infiltration (CD3+) was immunohistochemically assessed in retrospectively collected primary retinoblastomas. The efficacy of CAR-T cells targeting the CD171 and GD2 tumor-associated antigens was preclinically tested against three antigen-expressing retinoblastoma cell lines. CAR-T cell activation and exhaustion were assessed by cytokine release assays and flow cytometric detection of cell surface markers, and killing ability was assessed in cytotoxic assays. CAR constructs harboring different extracellular spacer lengths (short/long) and intracellular co-stimulatory domains (CD28/4-1BB) were compared to select the most potent constructs. RESULTS: All retinoblastoma cell lines investigated expressed CD171 and GD2. CD171 was expressed in 15/30 primary retinoblastomas. Retinoblastoma cell encounter strongly activated both CD171-specific and GD2-specific CAR-T cells. Targeting either CD171 or GD2 effectively killed all retinoblastoma cell lines examined. Similar activation and killing ability for either target was achieved by all CAR constructs irrespective of the length of the extracellular spacers and the co-stimulatory domain. Cell lines differentially lost tumor antigen expression upon CAR-T cell encounter, with CD171 being completely lost by all tested cell lines and GD2 further down-regulated in cell lines expressing low GD2 levels before CAR-T cell challenge. Alternating the CAR-T cell target in sequential challenges enhanced retinoblastoma cell killing. CONCLUSION: Both CD171 and GD2 are effective targets on human retinoblastoma cell lines, and CAR-T cell therapy is highly effective against retinoblastoma in vitro. Targeting of two different antigens by sequential CAR-T cell applications enhanced tumor cell killing and preempted tumor antigen loss in preclinical testing

Learning new sensorimotor contingencies:Effects of long-term use of sensory augmentation on the brain and conscious perception

Theories of embodied cognition propose that perception is shaped by sensory stimuli and by the actions of the organism. Following sensorimotor contingency theory, the mastery of lawful relations between own behavior and resulting changes in sensory signals, called sensorimotor contingencies, is constitutive of conscious perception. Sensorimotor contingency theory predicts that, after training, knowledge relating to new sensorimotor contingencies develops, leading to changes in the activation of sensorimotor systems, and concomitant changes in perception. In the present study, we spell out this hypothesis in detail and investigate whether it is possible to learn new sensorimotor contingencies by sensory augmentation. Specifically, we designed an fMRI compatible sensory augmentation device, the feelSpace belt, which gives orientation information about the direction of magnetic north via vibrotactile stimulation on the waist of participants. In a longitudinal study, participants trained with this belt for seven weeks in natural environment. Our EEG results indicate that training with the belt leads to changes in sleep architecture early in the training phase, compatible with the consolidation of procedural learning as well as increased sensorimotor processing and motor programming. The fMRI results suggest that training entails activity in sensory as well as higher motor centers and brain areas known to be involved in navigation. These neural changes are accompanied with changes in how space and the belt signal are perceived, as well as with increased trust in navigational ability. Thus, our data on physiological processes and subjective experiences are compatible with the hypothesis that new sensorimotor contingencies can be acquired using sensory augmentation

Über.Leben.Schreiben: Tradução e legendagem de uma live de literatura – Um projeto com estudantes de Letras português-alemão

This paper presents a subtitling and translation project carried out in the second academic semester of 2020 in the elective course “Translation German-Portuguese” at the Federal University of Rio de Janeiro. The basis for the students' evaluation was a three-part portfolio, prepared by them over the course of the semester, in which each of them reflected individually on their learning process. The main objective of the paper is to analyze the students' portfolios in terms of the main difficulties they encountered when translating, the perception of their progress of their German language skills, their language awareness, and their translation competence. Other objectives are to demonstrate the distinctive features of audiovisual translation and to analyze flaws in the organization of the project, in order to share experiences with other instructors interested in carrying out similar projects.Este artigo apresenta um projeto de tradução e legendagem realizado no segundo semestre de 2020 no âmbito da disciplina opcional “Tradução Alemão-Português” na Universidade Federal do Rio de Janeiro. A base para a avaliação dos(as) alunos(as) foi um portfólio contendo três relatórios escritos ao longo do semestre nos quais eles(as) refletiam individualmente sobre o próprio aprendizado. O objetivo principal do artigo é analisar os portfólios dos(as) alunos(as) em relação às principais dificuldades encontradas por eles(as) para executar a tarefa de tradução, às percepções de suas habilidades na língua alemã e a evolução da própria consciência linguística e de uma competência tradutória. Outros objetivos são demonstrar as particularidades da tradução audiovisual e analisar pontos frágeis da organização do projeto a fim de compartilhar experiências com outros(as) professores(as) interessados(as) em realizar projetos similares

Remote teaching in pandemic times: experiences with an emergency teacher training and its ramifications

The present article aims to describe an emergency teacher training that took place in July 2020 within the framework of the training of teachers of German as a foreign language (GFL) as part of the extension projects of three public universities in the state of Rio de Janeiro. The project was proposed and developed by teacher trainers from the three universities and was attended by undergraduate students working as teachers in the free language courses offered by the three participating institutions. The purpose of the training was to provide theoretical reflections and a practical introduction to online teaching, which, at that moment, was considered the only viable way of continuing to teach during the pandemic. This article will present the structure and content of the three weeks' training. Moreover, it presents and discusses the results of the evaluations given by the participants immediately after the course and one year later, in order to ascertain the role that the training may have had in their teaching practice.O presente artigo tem por objetivo descrever uma ação de formação emergencial que teve lugar em julho de 2020 no âmbito da formação de professores de alemão como língua estrangeira (ALE) nos projetos de extensão de três universidades públicas do estado do Rio de Janeiro. O projeto foi proposto e desenvolvido por professores-formadores das três universidades e teve a participação de graduandos das três instituições que atuavam nos cursos livres ofertados pelas instituições. O intuito do curso era fornecer reflexões teóricas e uma introdução prática ao trabalho online que se impunha então como única alternativa viável. Serão apresentados a estrutura do curso e os conteúdos trabalhados durante as três semanas de duração da formação. Além disso, serão discutidos igualmente os resultados das avaliações feitas pelos participantes do curso logo após o término e um ano após, a fim de se averiguar o papel que o curso possa ter tido na prática daqueles que participaram da formação

Can Bayesian Networks Improve Ground-Strike Point Classification?

Studying cloud-to-ground lightning strokes and ground-strike points provides an alternative method of lightning mapping for lightning risk assessment. Various k-means algorithms have been used to verify the ground-strike points from lightning locating systems, producing results with room for improvement. This paper proposes using Bayesian networks (BNs), a model not previously used for this purpose, to classify lightning ground-strike points. A Bayesian network is a probabilistic graphical model that uses Bayes’ theorem to represent the conditional dependencies of variables. The networks created for this research were trained from the data using a score-based structure-learning procedure and the Bayesian information criterion score function. The models were evaluated using confusion matrices and kappa indices and produced accuracy values ranging from 86% to 94% and kappa indices of up to 0.76. While BN models do not outperform k-means algorithms, they offer an alternative by not requiring predetermined distances. However, the easy implementation of the k-means approach means that no significant gain is made by implementing the more complex Bayesian network approach

Main effect and 2-way interactions in the fMRI data.

<p>Significant BOLD activation differences (the activation color-coding is depicted below the figures) in ROIs in z-, y-, x-planes (coordinates are depicted on top of each panel). (A) Main effect <i>belt</i> (on > off), (B) Main effect <i>date</i> (pre > post training), (C) Main effect <i>task</i> (homing > control task), (D) Main effect <i>group</i> (control > belt), (E) Interaction of <i>date</i> and <i>belt</i>, (F) Interaction of <i>date</i> and <i>task</i>. Captions color-coding ROIs in Fig 3(A)-(F): S1 lavender, S2 khaki, PPC light green, STG light gray, Insula baby blue, premotor cortex peach, SMA blue, cerebellum dark gray, caudate nucleus forest green, Hippocampus white, MST pink. (G-L) Blown ups of planes best depicting peak activations in ROIS of significant BOLD activation differences in two-way interactions: (G) Interaction <i>date x task</i>, peak activation of caudate nucleus, (H) Interaction <i>date x task</i>, peak activation of Cerebellum, (I) Interaction <i>date x belt</i>, peak activation of insula, (J) Interaction <i>date x belt</i>, peak activation of PPC, (K) Interaction <i>date x belt</i>, peak activation of MST, (L) Interaction <i>date x belt</i>, peak activation of S2, (S2 also depicted in I and K).</p

Factor ratings for the belt wearing and control group.

<p>Ratings for factors <i>trust in navigational ability</i> (black triangles), <i>tactile belt perception</i> (pink stars), <i>conscious belt perception</i> (light pentagons) and <i>space perception</i> (red circles) for the belt wearing group and <i>space perception</i> (blue squares) for the control group as a function of weeks. Ratings range from 1 to 5 (not agree to very agree), indicating a low or high rating for the factor, respectively. Dotted lines indicate fitted lines by a linear mixed model for each factor. Error bars are SEM.</p

Schematics of the fMRI path integration task.

<p>(A) Screenshot of the virtual environment and the response arrow. A surface texture of minimal-lifetime dots provides optic flow during outward journeys. (B) Triangles used in the outward journey traveld by subjects. The first segment of each triangle had constant velocity and a duration of 4s. The length of the second segment was adjusted according to the prior turning angle to ensure a total travel duration of 12s in all trials. (C) Flow of the conditions. During path integration, subjects should point the response arrow back to the starting location. During control, subjects should replicated the angle of an arrow additionally presented at the first static scene of control trials. Figures taken from Keyser [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0166647#pone.0166647.ref058" target="_blank">58</a>] and under Creative Commons CC-BY-3 from Schumann [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0166647#pone.0166647.ref031" target="_blank">31</a>].</p