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.

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.

[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.

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.

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.

Trim33/Tif1γ is involved in late stages of granulomonopoiesis in mice.

Trim33/Tif1γ (Trim33) is a member of the tripartite motif family. Using a conditional hematopoietic-specific Trim33 knock-out (Trim33(Δ/Δ)) mouse, we showed previously that Trim33 deficiency in hematopoietic stem cells leads to severe defects in hematopoiesis, resembling the main features of human chronic myelomonocytic leukemia. We also demonstrated that Trim33 is involved in hematopoietic aging through TGFß signaling. Nevertheless, how Trim33 contributes to the terminal stages of myeloid differentiation remains to be clarified. We reveal here the crucial role of Trim33 expression in the control of mature granulomonocytic differentiation. An important component of Trim33-deficient mice is the alteration of myeloid differentiation, as characterized by dysplastic features, abnormal granulocyte and monocyte maturation, and the expansion of CD11b(+)Ly6G(high)Ly6C(low) myeloid cells, which share some features with polymorphonuclear-myeloid-derived suppressor cells. Moreover, in Trim33(Δ/Δ) mice, we observed the alteration of CSF-1-mediated macrophage differentiation in association with the lack of Csf-1 receptor. Altogether, these results indicate that Trim33 deficiency leads to the expansion of a subset of myeloid cells characterizing the myelodysplastic/myeloproliferative neoplasm.

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.

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.

Student characteristics and behaviors at age 12 predict occupational success 40 years later over and above childhood IQ and parental socioeconomic status.

Drawing on a 2-wave longitudinal sample spanning 40 years from childhood (age 12) to middle adulthood (age 52), the present study was designed to examine how student characteristics and behaviors in late childhood (assessed in Wave 1 in 1968) predict career success in adulthood (assessed in Wave 2 in 2008). We examined the influence of parental socioeconomic status (SES), childhood intelligence, and student characteristics and behaviors (inattentiveness, school entitlement, responsible student, sense of inferiority, impatience, pessimism, rule breaking and defiance of parental authority, and teacher-rated studiousness) on 2 important real-life outcomes (i.e., occupational success and income). The longitudinal sample consisted of N = 745 persons who participated in 1968 (M = 11.9 years, SD = 0.6; 49.9% female) and 2008 (M = 51.8 years, SD = 0.6; 53.3% female). Regression analyses and path analyses were conducted to evaluate the direct and indirect effects (via education) of the predictors on career success. The results revealed direct and indirect influences of student characteristics (responsible student, rule breaking and defiance of parental authority, and teacher-rated studiousness) across the life span on career success after adjusting for differences in parental SES and IQ at age 12. rd

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.

Executive functioning and reading achievement in school: a study of Brazilian children assessed by their teachers as "poor readers".

This study examined executive functioning and reading achievement in 106 6- to 8-year-old Brazilian children from a range of social backgrounds of whom approximately half lived below the poverty line. A particular focus was to explore the executive function profile of children whose classroom reading performance was judged below standard by their teachers and who were matched to controls on chronological age, sex, school type (private or public), domicile (Salvador/BA or São Paulo/SP) and socioeconomic status. Children completed a battery of 12 executive function tasks that were conceptual tapping cognitive flexibility, working memory, inhibition and selective attention. Each executive function domain was assessed by several tasks. Principal component analysis extracted four factors that were labeled "Working Memory/Cognitive Flexibility," "Interference Suppression," "Selective Attention," and "Response Inhibition." Individual differences in executive functioning components made differential contributions to early reading achievement. The Working Memory/Cognitive Flexibility factor emerged as the best predictor of reading. Group comparisons on computed factor scores showed that struggling readers displayed limitations in Working Memory/Cognitive Flexibility, but not in other executive function components, compared to more skilled readers. These results validate the account that working memory capacity provides a crucial building block for the development of early literacy skills and extends it to a population of early readers of Portuguese from Brazil. The study suggests that deficits in working memory/cognitive flexibility might represent one contributing factor to reading difficulties in early readers. This might have important implications for how educators might intervene with children at risk of academic under achievement.

Predicting first-grade mathematics achievement: the contributions of domain-general cognitive abilities, nonverbal number sense, and early number competence.

Early number competence, grounded in number-specific and domain-general cognitive abilities, is theorized to lay the foundation for later math achievement. Few longitudinal studies have tested a comprehensive model for early math development. Using structural equation modeling and mediation analyses, the present work examined the influence of kindergarteners' nonverbal number sense and domain-general abilities (i.e., working memory, fluid intelligence, and receptive vocabulary) and their early number competence (i.e., symbolic number skills) on first grade math achievement (i.e., arithmetic, shape and space skills, and number line estimation) assessed 1 year later. Latent regression models revealed that nonverbal number sense and working memory are central building blocks for developing early number competence in kindergarten and that early number competence is key for first grade math achievement. After controlling for early number competence, fluid intelligence significantly predicted arithmetic and number line estimation while receptive vocabulary significantly predicted shape and space skills. In sum we suggest that early math achievement draws on different constellations of number-specific and domain-general mechanisms.

The impact of mathematical proficiency on the number-space association.

A specific instance of the association between numerical and spatial representations is the SNARC (Spatial Numerical Association of Response Codes) effect. The SNARC effect describes the finding that during binary classification of numbers participants are faster to respond to small/large numbers with the left/right hand respectively. Even though it has been frequently replicated, important inter-individual variability has also been reported. Mathematical proficiency is an obvious candidate source for inter-individual variability in numerical judgments, but studies investigating its influence on the SNARC effect remain scarce. The present experiment included a total of 95 University students, divided into three groups differing significantly in their mathematical proficiency levels. Using group analyses, it appeared that the three groups differed significantly in the strength of their number-space associations in a parity judgment task. This result was further confirmed on an individual level, with higher levels in arithmetic leading to relatively weaker SNARC effects. To explain this negative relationship we propose accounts based on differences in access to qualitatively different numerical representations and also consider more domain general factors, with a focus on inhibition capacities.

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.

Forty years on: childhood intelligence predicts health in middle adulthood.

OBJECTIVE: To investigate whether childhood general intelligence, fluid intelligence (Gf), and crystallized intelligence (Gc) predict various health outcomes in middle adulthood. METHOD: This prospective longitudinal study followed a nationally representative sample of 717 Luxembourgers. Intelligence and socioeconomic status (SES) were measured at age 12; physical, functional, and subjective health were assessed at age 52. RESULTS: Childhood general intelligence and fluid intelligence showed substantial positive effects on adult health outcomes, whereas the corresponding effects of crystallized intelligence were considerably smaller. CONCLUSION: Childhood intelligence incrementally predicts various dimensions of adult health across 40 years-even in a country in which all citizens are guaranteed access to high-quality health care.