Treatment of HCC with claudin-1-specific antibodies suppresses carcinogenic signaling and reprograms the tumor microenvironment.

BACKGROUND & AIMS: Despite recent approvals, the response to treatment and prognosis of patients with advanced hepatocellular carcinoma (HCC) remain poor. Claudin-1 (CLDN1) is a membrane protein that is expressed at tight junctions, but it can also be exposed non-junctionally, such as on the basolateral membrane of the human hepatocyte. While CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 and its role as a therapeutic target in HCC remains unexplored. METHODS: Using humanized monoclonal antibodies (mAbs) specifically targeting the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as a therapeutic target for HCC. RESULTS: Targeting non-junctional CLDN1 markedly suppressed tumor growth and invasion in cell line-based models of HCC and patient-derived 3D ex vivo models. Moreover, the robust effect on tumor growth was confirmed in vivo in a large series of cell line-derived xenograft and patient-derived xenograft mouse models. Mechanistic studies, including single-cell RNA sequencing of multicellular patient HCC tumorspheres, suggested that CLDN1 regulates tumor stemness, metabolism, oncogenic signaling and perturbs the tumor immune microenvironment. CONCLUSIONS: Our results provide the rationale for targeting CLDN1 in HCC and pave the way for the clinical development of CLDN1-specific mAbs for the treatment of advanced HCC. IMPACT AND IMPLICATIONS: Hepatocellular carcinoma (HCC) is associated with high mortality and unsatisfactory treatment options. Herein, we identified the cell surface protein Claudin-1 as a treatment target for advanced HCC. Monoclonal antibodies targeting Claudin-1 inhibit tumor growth in patient-derived ex vivo and in vivo models by modulating signaling, cell stemness and the tumor immune microenvironment. Given the differentiated mechanism of action, the identification of Claudin-1 as a novel therapeutic target for HCC provides an opportunity to break the plateau of limited treatment response. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of advanced HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology.

The number line estimation task is a valid tool for assessing mathematical achievement: A population-level study with 6484 Luxembourgish ninth-graders.

The number line estimation task is an often-used measure of numerical magnitude understanding. The task also correlates substantially with broader measures of mathematical achievement. This raises the question of whether the task would be a useful component of mathematical achievement tests and instruments to diagnose dyscalculia or mathematical giftedness and whether a stand-alone version of the task can serve as a short screener for mathematical achievement. Previous studies on the relation between number line estimation accuracy and broader mathematical achievement were limited in that they used relatively small nonrepresentative samples and usually did not account for potentially confounding variables. To close this research gap, we report findings from a population-level study with nearly all Luxembourgish ninth-graders (N = 6484). We used multilevel regressions to test how a standardized mathematical achievement test relates to the accuracy in number line estimation on bounded number lines with whole numbers and fractions. We also investigated how these relations were moderated by classroom characteristics, person characteristics, and trial characteristics. Mathematical achievement and number line estimation accuracy were associated even after controlling for potentially confounding variables. Subpopulations of students showed meaningful differences in estimation accuracy, which can serve as benchmarks in future studies. Compared with the number line estimation task with whole numbers, the number line estimation task with fractions was more strongly related to mathematical achievement in students across the entire mathematical achievement spectrum. These results show that the number line estimation task is a valid and useful tool for diagnosing and monitoring mathematical achievement.

Visuo-spatial abilities are key for young children's verbal number skills.

Children's development of verbal number skills (i.e., counting abilities and knowledge of the number names) presents a milestone in mathematical development. Different factors such as visuo-spatial and verbal abilities have been discussed as contributing to the development of these foundational skills. To understand the cognitive nature of verbal number skills in young children, the current study assessed the relation of preschoolers' verbal and visuo-spatial abilities to their verbal number skills. In total, 141 children aged 5 or 6 years participated in the current study. Verbal number skills were regressed on vocabulary, phonological awareness and visuo-spatial abilities, and verbal and visuo-spatial working memory in a structural equation model. Only visuo-spatial abilities emerged as a significant predictor of verbal number skills in the estimated model. Our results suggest that visuo-spatial abilities contribute to a larger extent to children's verbal number skills than verbal abilities. From a theoretical point of view, these results suggest a visuo-spatial, rather than a verbal, grounding of verbal number skills. These results are potentially informative for the conception of early mathematics assessments and interventions.

Tif1γ regulates the TGF-ß1 receptor and promotes physiological aging of hematopoietic stem cells.

The hematopoietic system declines with age. Myeloid-biased differentiation and increased incidence of myeloid malignancies feature aging of hematopoietic stem cells (HSCs), but the mechanisms involved remain uncertain. Here, we report that 4-mo-old mice deleted for transcription intermediary factor 1γ (Tif1γ) in HSCs developed an accelerated aging phenotype. To reinforce this result, we also show that Tif1γ is down-regulated in HSCs during aging in 20-mo-old wild-type mice. We established that Tif1γ controls TGF-ß1 receptor (Tgfbr1) turnover. Compared with young HSCs, Tif1γ(-/-) and old HSCs are more sensitive to TGF-ß signaling. Importantly, we identified two populations of HSCs specifically discriminated by Tgfbr1 expression level and provided evidence of the capture of myeloid-biased (Tgfbr1(hi)) and myeloid-lymphoid-balanced (Tgfbr1(lo)) HSCs. In conclusion, our data provide a new paradigm for Tif1γ in regulating the balance between lymphoid- and myeloid-derived HSCs through TGF-ß signaling, leading to HSC aging.

The Kind of Student You Were in Elementary School Predicts Mortality.

We examined the association of self-reported and teacher-rated student characteristics assessed at the end of primary school with all-cause mortality assessed through age 52. Data stem from a representative sample of students from Luxembourg assessed in 1968 (N = 2,543; M = 11.9 years, SD = 0.6; 49.9% female; N = 166 participants died). Results from logistic regression analyses showed that the self-reported responsible student scale (OR = .81; CI = [.70; .95]) and the teacher rating of studiousness (OR = .80; CI = [.67; .96]) were predictive for all-cause mortality even after controlling for IQ, parental SES, and sex. These findings indicate that both observer-rated and self-reported student behaviors are important life-course predictors for mortality and are perhaps more important than childhood IQ.

A role for miR-142-3p in colony-stimulating factor 1-induced monocyte differentiation into macrophages.

The differentiation of human peripheral blood monocytes into macrophages can be reproduced ex vivo by culturing the cells in the presence of colony-stimulating factor 1 (CSF1). Using microarray profiling to explore the role of microRNAs (miRNAs), we identified a dramatic decrease in the expression of the hematopoietic specific miR-142-3p. Up- and down-regulation of this miRNA in primary human monocytes altered CSF1-induced differentiation of monocytes, as demonstrated by changes in the expression of the cell surface markers CD16 and CD163. One of the genes whose expression is repressed by miR-142-3p encodes the transcription factor Early Growth Response 2 (Egr2). In turn, Egr2 associated with its co-repressor NGFI-A (Nerve Growth Factor-Induced gene-A) binding protein 2 (NAB2) binds to the pre-miR-142-3p promoter to negatively regulate its expression. Interestingly, the expression of miR-142-3p is abnormally low in monocytes from patients with the most proliferative forms of chronic myelomonocytic leukemia (CMML), and miR-142-3p re-expression in CMML dysplastic monocytes can improve their differentiation potential. Altogether, miR-142-3p which functions in a molecular circuitry with Egr2 is an actor of CSF1-induced differentiation of human monocytes whose expression could be altered in CMML.

Symplekin, a polyadenylation factor, prevents MOZ and MLL activity on HOXA9 in hematopoietic cells.

MOZ and MLL encoding a histone acetyltransferase and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. We have previously shown that MOZ and MLL cooperate to activate HOXA9 gene expression in hematopoietic stem/progenitors cells. To dissect the mechanism of action of this complex, we decided to identify new proteins interacting with MOZ. We found that the scaffold protein Symplekin that supports the assembly of polyadenylation machinery was identified by mass spectrometry. Symplekin interacts and co-localizes with both MOZ and MLL in immature hematopoietic cells. Its inhibition leads to a decrease of the HOXA9 protein level but not of Hoxa9 mRNA and to an over-recruitment of MOZ and MLL onto the HOXA9 promoter. Altogether, our results highlight the role of Symplekin in transcription repression involving a regulatory network between MOZ, MLL and Symplekin.

Effects of impoverished environmental conditions on working memory performance.

This cross-cultural study investigates the impact of background experience on four verbal and visuo-spatial working memory (WM) tasks. A total of 84 children from low-income families were recruited from the following groups: (1) Portuguese immigrant children from Luxembourg impoverished in terms of language experience; (2) Brazilian children deprived in terms of scholastic background; (3) Portuguese children from Portugal with no disadvantage in either scholastic or language background. Children were matched on age, gender, fluid intelligence, and socioeconomic status and completed four simple and complex span tasks of WM and a vocabulary measure. Results indicate that, despite large differences in their backgrounds and language abilities, the groups exhibited comparable performance on the visuo-spatial tasks dot matrix and odd-one-out and on the verbal simple span task digit recall. Group differences emerged on the verbal complex span task counting recall with children from Luxembourg and Portugal outperforming children from disadvantaged schools in Brazil. The study suggests that whereas contributions of prior knowledge to digit span, dot matrix, and odd-one-out are likely to be minimal, background experience can affect performance on counting recall. Implications for testing WM capacity in children growing up in poverty are discussed.

Developing number-space associations: SNARC effects using a color discrimination task in 5-year-olds.

Human adults' numerical representation is spatially oriented; consequently, participants are faster to respond to small/large numerals with their left/right hand, respectively, when doing a binary classification judgment on numbers, known as the SNARC (spatial-numerical association of response codes) effect. Studies on the emergence and development of the SNARC effect remain scarce. The current study introduces an innovative new paradigm based on a simple color judgment of Arabic digits. Using this task, we found a SNARC effect in children as young as 5.5 years. In contrast, when preschool children needed to perform a magnitude judgment task necessitating exact number knowledge, the SNARC effect started to emerge only at 5.8 years. Moreover, the emergence of a magnitude SNARC but not a color SNARC was linked to proficiency with Arabic digits. Our results suggest that access to a spatially oriented approximate magnitude representation from symbolic digits emerges early in ontogenetic development. Exact magnitude judgments, on the other hand, rely on experience with Arabic digits and, thus, necessitate formal or informal schooling to give access to a spatially oriented numerical representation.

Bilingualism enriches the poor: enhanced cognitive control in low-income minority children.

This study explores whether the cognitive advantage associated with bilingualism in executive functioning extends to young immigrant children challenged by poverty and, if it does, which specific processes are most affected. In the study reported here, 40 Portuguese-Luxembourgish bilingual children from low-income immigrant families in Luxembourg and 40 matched monolingual children from Portugal completed visuospatial tests of working memory, abstract reasoning, selective attention, and interference suppression. Two broad cognitive factors of executive functioning-representation (abstract reasoning and working memory) and control (selective attention and interference suppression)-emerged from principal component analysis. Whereas there were no group differences in representation, the bilinguals performed significantly better than did the monolinguals in control. These results demonstrate, first, that the bilingual advantage is neither confounded with nor limited by socioeconomic and cultural factors and, second, that separable aspects of executive functioning are differentially affected by bilingualism. The bilingual advantage lies in control but not in visuospatial representational processes.

How can we enhance girls' interest in scientific topics?

BACKGROUND: Girls are considerably less interested in scientific subjects than boys. One reason may be that scientific subjects are considered to be genuinely masculine. Thus, being interested in science may threaten the self-perception of girls as well as the femininity of their self-image. AIMS: If scientific topics that are considered to be stereotypically feminine were chosen, however, this potential threat might be overcome which, in turn, might lead to an increase in girls' interest in science. This hypothesis was empirically tested by means of two studies. SAMPLE: Participants were 294 (Study 1) and 190 (Study 2) Grade 8 to Grade 9 students. METHOD: Gender differences in students' interest in masculine and feminine topics were investigated for a range of scientific concepts (Study 1) as well as for a given scientific concept (Study 2) for four scientific subjects (i.e., biology, physics, information technology, and statistics), respectively. RESULTS: Both studies indicated that the mean level of girls' scientific interest was higher when scientific concepts were presented in the context of feminine topics and boys' level of scientific interests was higher when scientific concepts were presented in the context of masculine topics. CONCLUSION: Girls' interest in science could be substantially increased by presenting scientific concepts in the context of feminine topics. Gender differences as well as individual differences in the level of interest in scientific topics may be taken into account by creating learning environments in which students could select the context in which a certain scientific concept is embedded.

Is there continuity between categorical and coordinate spatial relations coding? Evidence from a grid/no-grid working memory paradigm.

We ask the question whether the coding of categorical versus coordinate spatial relations depends on different neural networks showing hemispheric specialization or whether there is continuity between these two coding types. The 'continuous spatial coding' hypothesis would mean that the two coding types rely essentially on the same neural network consisting of more general-purpose processes, such as visuo-spatial attention, but with a different weighting of these general processes depending on exact task requirements. With event-related fMRI, we have studied right-handed male subjects performing a grid/no-grid visuo-spatial working memory task inducing categorical and coordinate spatial relations coding. Our data support the 'continuous spatial coding' hypothesis, indicating that, while based on the same fronto-parieto-occipital neural network than categorical spatial relations coding, the coding of coordinate spatial relations relies more heavily on attentional and executive processes, which could induce hemispheric differences similar to those described in the literature. The results also show that visuo-spatial working memory consists of a short-term posterior store with a capacity of up to three elements in the parietal and extrastriate cortices. This store depends on the presence of a visible space categorization and thus can be used for the coding of categorical spatial relations. When no visible space categorization is given or when more than three elements have to be coded, additional attentional and executive processes are recruited, mainly located in the dorso-lateral prefrontal cortex.

[Lower-extremity artery disease (LEAD)]. / L'artériopathie oblitérante des membres inférieurs chez la femme.

Women have a risk of LEAD (lower-extremity artery disease)similar to men's risk. Symptoms are often absent, atypical or underestimated, leading to diagnosis in the most severe stages. Medical care is often less well adapted. In cases of revascularization, women have a higher morbidity rate than men, regardless of the severity grade and procedure chosen.

Taking Language out of the Equation: The Assessment of Basic Math Competence Without Language.

While numerical skills are fundamental in modern societies, some estimated 5-7% of children suffer from mathematical learning difficulties (MLD) that need to be assessed early to ensure successful remediation. Universally employable diagnostic tools are yet lacking, as current test batteries for basic mathematics assessment are based on verbal instructions. However, prior research has shown that performance in mathematics assessment is often dependent on the testee's proficiency in the language of instruction which might lead to unfair bias in test scores. Furthermore, language-dependent assessment tools produce results that are not easily comparable across countries. Here we present results of a study that aims to develop tasks allowing to test for basic math competence without relying on verbal instructions or task content. We implemented video and animation-based task instructions on touchscreen devices that require no verbal explanation. We administered these experimental tasks to two samples of children attending the first grade of primary school. One group completed the tasks with verbal instructions while another group received video instructions showing a person successfully completing the task. We assessed task comprehension and usability aspects both directly and indirectly. Our results suggest that the non-verbal instructions were generally well understood as the absence of explicit verbal instructions did not influence task performance. Thus we found that it is possible to assess basic math competence without verbal instructions. It also appeared that in some cases a single word in a verbal instruction can lead to the failure of a task that is successfully completed with non-verbal instruction. However, special care must be taken during task design because on rare occasions non-verbal video instructions fail to convey task instructions as clearly as spoken language and thus the latter do not provide a panacea to non-verbal assessment. Nevertheless, our findings provide an encouraging proof of concept for the further development of non-verbal assessment tools for basic math competence.

Eye Movements and Cognitive Strategy in a Fluid Intelligence Test: Item Type Analysis.

Eye movements help to infer the cognitive strategy that a person uses in fluid intelligence tests. However, intelligence tests demand different relations/rules tokens to be solved, such as rule direction, which is the continuation, variation or overlay of geometric figures in the matrix of the intelligence test. The aim of this study was to understand whether eye movements could predict the outcome of an intelligence test and in the rule item groups. Furthermore, we sought to identify which measure is best for predicting intelligence test scores and to understand if the rule item groups use the same strategy. Accordingly, 34 adults completed a computerized intelligence test with an eye-tracking device. The toggling rate, that is, the number of toggles on each test item equalized by the item latency explained 45% of the variance of the test scores and a significant amount of the rule tokens item groups. The regression analyses also indicated toggling rate as the best measure for predicting the score and that all the rule tokens seem to respect the same strategy. No correlation or difference were found between baseline pupil size and fluid intelligence. Wiener Matrizen-Test 2 was demonstrated to be a good instrument for the purpose of this study. Finally, the implications of these findings for an understanding of cognition are discussed.

General and Specific Contributions of RAN to Reading and Arithmetic Fluency in First Graders: A Longitudinal Latent Variable Approach.

In the present study, we opted for a longitudinal design and examined rapid automatized naming (RAN) performance from two perspectives. In a first step, we examined the structure of RAN performance from a general cognitive perspective. We investigated whether rapid naming measures (e.g., digit RAN and color RAN) reflect a mainly domain-general factor or domain-specific factors. In a second step, we examined how the best fitting RAN model was related to reading and arithmetic outcomes, assessed several months later. Finally in a third step we took a clinical perspective and investigated specific contributions of RAN measures to reading and arithmetic outcomes. While RAN has emerged as a promising predictor of reading, the relationship between RAN and arithmetic has been less examined in the past. Hundred and twenty-two first graders completed seven RAN tasks, each comprising visually familiar stimuli such as digits, vowels, consonants, dice, finger-numeral configurations, objects, and colors. Four months later the same children completed a range of reading and arithmetic tasks. From a general descriptive perspective, structural equation modeling supports a one-dimensional RAN factor in 6- to -7-year-old children. However, from a clinical perspective, our findings emphasize the specific contributions of RANs. Interestingly, alphanumeric RANs (i.e., vowel RAN) were most promising when predicting reading skills and number-specific RANs (i.e., finger-numeral configuration RAN) were most promising when predicting arithmetic fluency. The implications for clinical and educational practices will be discussed.

Sometimes More is Too Much: A Rejoinder to the Commentaries on Greiff et al. (2015).

In this rejoinder, we respond to two commentaries on the study by Greiff, S.; Stadler, M.; Sonnleitner, P.; Wolff, C.; Martin, R. Sometimes less is more: Comparing the validity of complex problem solving measures. Intelligence 2015, 50, 100-113. The study was the first to address the important comparison between a classical measure of complex problem solving (CPS) and the more recent multiple complex systems (MCS) approach regarding their validity. In the study, we investigated the relations between one classical microworld as the initially developed method (here, the Tailorshop) with three more recently developed multiple complex systems (MCS; here, MicroDYN, Genetics Lab, and MicroFIN) tests. We found that the MCS tests showed higher levels of convergent validity with each other than with the Tailorshop even after reasoning was controlled for, thus empirically distinguishing between the two approaches. The commentary by Kretzschmar and the commentary by Funke, Fischer, and Holt expressed several concerns with how our study was conducted, our data was analyzed, and our results were interpreted. Whereas we acknowledge and agree with some of the more general statements made in these commentaries, we respectfully disagree with others, or we consider them to be at least partially in contrast with the existing literature and the currently available empirical evidence.

Developmental Dynamics of General and School-Subject-Specific Components of Academic Self-Concept, Academic Interest, and Academic Anxiety.

The present study investigated the developmental dynamics of general and subject-specific (i.e., mathematics, French, and German) components of students' academic self-concept, anxiety, and interest. To this end, the authors integrated three lines of research: (a) hierarchical and multidimensional approaches to the conceptualization of each construct, (b) longitudinal analyses of bottom-up and top-down developmental processes across hierarchical levels, and (c) developmental processes across subjects. The data stemmed from two longitudinal large-scale samples (N = 3498 and N = 3863) of students attending Grades 7 and 9 in Luxembourgish schools. Nested-factor models were applied to represent each construct at each grade level. The analyses demonstrated that several characteristics were shared across constructs. All constructs were multidimensional in nature with respect to the different subjects, showed a hierarchical organization with a general component at the apex of the hierarchy, and had a strong separation between the subject-specific components at both grade levels. Further, all constructs showed moderate differential stabilities at both the general (0.42 < r < 0.55) and subject-specific levels (0.45 < r < 0.73). Further, little evidence was found for top-down or bottom-up developmental processes. Rather, general and subject-specific components in Grade 9 proved to be primarily a function of the corresponding components in Grade 7. Finally, change in several subject-specific components could be explained by negative effects across subjects.