Targeting integrins in drug-resistant acute myeloid leukaemia.

Acute myeloid leukaemia (AML) continues to have a poor prognosis, warranting new therapeutic strategies. The bone marrow (BM) microenvironment consists of niches that interact with not only normal haematopoietic stem cells (HSC) but also leukaemia cells like AML. There are many adhesion molecules in the BM microenvironment; therein, integrins have been of central interest. AML cells express integrins that bind to ligands in the microenvironment, enabling adhesion of leukaemia cells in the microenvironment, thereby initiating intracellular signalling pathways that are associated with cell migration, cell proliferation, survival, and drug resistance that has been described to mediate cell adhesion-mediated drug resistance (CAM-DR). Identifying and targeting integrins in AML to interrupt interactions with the microenvironment have been pursued as a strategy to overcome CAM-DR. Here, we focus on the BM microenvironment and review the role of integrins in CAM-DR of AML and discuss integrin-targeting strategies. LINKED ARTICLES: This article is part of a themed issue on Cancer Microenvironment and Pharmacological Interventions. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.2/issuetoc.

White matter microstructure on diffusion tensor imaging is associated with conventional magnetic resonance imaging findings and cognitive function in adolescents born preterm.

AIM: Diffusion tensor imaging (DTI) was used to evaluate white matter architecture after preterm birth. The goals were (1) to compare white matter microstructure in two cohorts of preterm- and term-born children; and (2) within preterm groups, to determine if sex, gestational age, birthweight, white matter injury score from conventional magnetic resonance imaging (MRI), or IQ was associated with DTI measures. METHOD: Participants (n=121; 66 females, 55 males) were aged 9 to 16 years. They comprised 58 preterm children (site 1, n=25; and site 2, n=33) born at less than 36 weeks' gestation (mean 29.4 wks; birthweight 1289g) and 63 term children (site 1, n=40; site 2, n=23) born at more than 37 weeks' gestation. DTI was analyzed using tract-based spatial statistics. Diffusion measures were fractional anisotropy, axial, radial, and mean diffusivity. RESULTS: In no region of the white matter skeleton was fractional anisotropy lower in the preterm group at either site. Within the preterm groups, fractional anisotropy was significantly associated with white matter injury score, but not sex, gestational age, or birthweight. At site 1, fractional anisotropy was associated with IQ. INTERPRETATION: DTI contributes to understanding individual differences after preterm birth but may not differentiate a relatively high-functioning group of preterm children from a matched group of term-born children.

Attention and internalizing behaviors in relation to white matter in children born preterm.

OBJECTIVE: Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that provides quantitative characterization of white matter tracts in the brain. This study used DTI to examine the degree of association between parent-rated scores of attention, internalizing behaviors including anxiety symptoms, and externalizing behaviors and white matter fractional anisotropy (FA) in children born preterm. METHODS: Participants were aged 9 to 16 years; 25 were born at <36 weeks of gestation (mean = 28.6 wk, birth weight = 1191 g) and 20 were full term. The authors analyzed the results using Tract-Based Spatial Statistics, a technique that generates a skeleton representing the core of white matter tracts throughout the brain. The authors examined the correlations between behavior scores and FA of (1) the whole skeleton and (2) the specific regions of interest. RESULTS: In preterm children, scores on attention and internalizing behavior scales were each associated with whole skeleton FA and several regions of interest; unfavorable scores were consistently associated with lower FA. Externalizing behaviors were not associated with whole skeleton FA, but significant associations were found within a few regions of interest. The network of significant regions for attention and internalizing symptoms was widely distributed and overlapping. In full-term children, no associations of FA and behavior were significant. CONCLUSIONS: Attention and internalizing behaviors in preterm children were associated with FA in a widely distributed overlapping network of white matter tracts, suggesting common underlying neurobiology. DTI contributes to understanding individual differences in attention and behavior characteristics in children born preterm.

Language and reading skills in school-aged children and adolescents born preterm are associated with white matter properties on diffusion tensor imaging.

Children born preterm are at risk for deficits in language and reading. They are also at risk for injury to the white matter of the brain. The goal of this study was to determine whether performance in language and reading skills would be associated with white matter properties in children born preterm and full-term. Children born before 36 weeks gestation (n=23, mean±SD age 12.5±2.0 years, gestational age 28.7±2.5 weeks, birth weight 1184±431 g) and controls born after 37 weeks gestation (n=19, 13.1±2.1 years, 39.3±1.0 weeks, 3178±413 g) underwent a battery of language and reading tests. Diffusion tensor imaging (DTI) scans were processed using tract-based spatial statistics to generate a core white matter skeleton that was anatomically comparable across participants. Fractional anisotropy (FA) was the diffusion property used in analyses. In the full-term group, no regions of the whole FA-skeleton were associated with language and reading. In the preterm group, regions of the FA-skeleton were significantly associated with verbal IQ, linguistic processing speed, syntactic comprehension, and decoding. Combined, the regions formed a composite map of 22 clusters on 15 tracts in both hemispheres and in the ventral and dorsal streams. ROI analyses in the preterm group found that several of these regions also showed positive associations with receptive vocabulary, verbal memory, and reading comprehension. Some of the same regions showed weak negative correlations within the full-term group. Exploratory multiple regression in the preterm group found that specific white matter pathways were related to different aspects of language processing and reading, accounting for 27-44% of the variance. The findings suggest that higher performance in language and reading in a group of preterm but not full-term children is associated with higher fractional anisotropy of a bilateral and distributed white matter network.

Executive function skills are associated with reading and parent-rated child function in children born prematurely.

BACKGROUND: Preterm children are at risk for executive function (EF) problems, which have been linked to behavior and learning problems in full term children. In this study, we examine the relationship between EF and functional outcomes in preterm children. AIM: To evaluate (1) EF skills of 9- to 16-year-old children born across the spectrum of gestational age (GA), (2) relationship of degree of prematurity to EF skills, and (3) contributions of EF skills to two functional outcomes - reading scores and parent-rated child function. METHOD: Preterm children <36 weeks gestation (n=72) were compared to full term children (n=42) of similar age, gender and SES, on measures of EF, reading, and parent-ratings of child function. Multiple regression models evaluated contributions to EF skills and functional outcomes. RESULTS: Compared to full term controls, preterm children had poorer EF performance on a complex planning and organization task and did not increase planning time as task difficulty increased. Their spatial memory capacity was not different. GA contributed to EF skills, but was mediated by IQ. EF contributed to the variance in reading skills but did not add to the variance in reading when IQ was considered. EF skills significantly contributed to the variance in parent-rated child function, but IQ did not. CONCLUSION: EF skills contribute to measures of functional outcome in this high-risk population. The use of EF skills as an early marker for learning and functional problems and as a target for intervention in children born preterm warrants future study.

Differences in neural activation between preterm and full term born adolescents on a sentence comprehension task: implications for educational accommodations.

Adolescent survivors of preterm birth experience persistent functional problems that negatively impact academic outcomes, even when standardized measures of cognition and language suggest normal ability. In this fMRI study, we compared the neural activation supporting auditory sentence comprehension in two groups of adolescents (ages 9-16 years); sentences varied in length and syntactic difficulty. Preterms (n=18, mean gestational age 28.8 weeks) and full terms (n=14) had scores on verbal IQ, receptive vocabulary, and receptive language tests that were within or above normal limits and similar between groups. In early and late phases of the trial, we found interactions by group and length; in the late phase, we also found a group by syntactic difficulty interaction. Post hoc tests revealed that preterms demonstrated significant activation in the left and right middle frontal gyri as syntactic difficulty increased. ANCOVA showed that the interactions could not be attributed to differences in age, receptive language skill, or reaction time. Results are consistent with the hypothesis that preterm birth modulates brain-behavior relations in sentence comprehension as task demands increase. We suggest preterms' differences in neural processing may indicate a need for educational accommodations, even when formal test scores indicate normal academic achievement.

Behavior problems of 9-16 year old preterm children: biological, sociodemographic, and intellectual contributions.

BACKGROUND: Preterm children are at risk for behavior problems. Studies examining contributions of intellectual and environmental factors to behavior outcomes in preterm children are mixed. AIMS: (1) To identify the nature of maladaptive behaviors in preterm children age 9 to 16 years born across the spectrum of gestational age and birth weight (BW). (2) To examine contributions of BW as a biological factor, socioeconomic status as an environmental factor, and intelligence quotient (IQ) as indicative of intellectual ability to behavior outcomes. METHOD: Using the Child Behavior Checklist, parent reports of behavior for 63 preterm children (gestational age 24 to <36 weeks) were compared to 29 full term children of similar age, gender and socioeconomic status. Multiple regression models evaluated effects of prematurity, socioeconomic status, and intellectual ability on behavioral symptom scores. RESULTS: Preterm children had higher total and internalizing problem scores compared to full term children. They also had lower IQ. BW was a significant predictor of total and internalizing behavior problems. Among the syndrome scales, anxious/depressed and attention problems were elevated. Socioeconomic status did not contribute to behavior scores. IQ contributed to total, but not to internalizing or externalizing, scores. IQ contributed to attention problems, but not to anxious/depressed scores. CONCLUSION: Preterm children had increased behavior problems, especially symptoms of inattention and anxiety. Lower BW predicted more behavior problems. IQ acted as a mediator between BW and attention scores, but not anxiety scores. These findings alert health care providers to assess anxiety in all preterm children regardless of intellectual ability and additional study on the influence of intellectual ability on behavioral outcomes in preterm children is needed.

Specific language and reading skills in school-aged children and adolescents are associated with prematurity after controlling for IQ.

Although studies of long-term outcomes of children born preterm consistently show low intelligence quotient (IQ) and visual-motor impairment, studies of their performance in language and reading have found inconsistent results. In this study, we examined which specific language and reading skills were associated with prematurity independent of the effects of gender, socioeconomic status (SES), and IQ. Participants from two study sites (N=100) included 9-16-year old children born before 36 weeks gestation and weighing less than 2500 grams (preterm group, n=65) compared to children born at 37 weeks gestation or more (full-term group, n=35). Children born preterm had significantly lower scores than full-term controls on Performance IQ, Verbal IQ, receptive and expressive language skills, syntactic comprehension, linguistic processing speed, verbal memory, decoding, and reading comprehension but not on receptive vocabulary. Using MANCOVA, we found that SES, IQ, and prematurity all contributed to the variance in scores on a set of six non-overlapping measures of language and reading. Simple regression analyses found that after controlling for SES and Performance IQ, the degree of prematurity as measured by gestational age group was a significant predictor of linguistic processing speed, ß=-.27, p<.05, R(2)=.07, verbal memory, ß=.31, p<.05, R(2)=.09, and reading comprehension, ß=.28, p<.05, R(2)=.08, but not of receptive vocabulary, syntactic comprehension, or decoding. The language and reading domains where prematurity had a direct effect can be classified as fluid as opposed to crystallized functions and should be monitored in school-aged children and adolescents born preterm.

Diffusion tensor imaging: a review for pediatric researchers and clinicians.

Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that allows for the visualization and characterization of the white matter tracts of the brain in vivo. DTI does not assess white matter directly. Rather, it capitalizes on the fact that diffusion is isotropic (equal in all directions) in cerebral spinal fluid and cell bodies but anisotropic (greater in one direction than the other directions) in axons that comprise white matter. It provides quantitative information about the degree and direction of water diffusion within individual units of volume within the magnetic resonance image, and by inference, about the integrity of white matter. Measures from DTI can be applied throughout the brain or to regions of interest. Fiber tract reconstruction, or tractography, creates continuous 3-dimensional tracts by sequentially piecing together estimates of fiber orientation from the direction of diffusion within individual volume units. DTI has increased our understanding of white matter structure and function. DTI shows nonlinear growth of white matter tracts from childhood to adulthood. Delayed maturation of the white matter in the frontal lobes may explain the continued growth of cognitive control into adulthood. Relative to good readers, adults and children who are poor readers have evidence of white matter differences in a specific region of the temporo-parietal lobe, implicating differences in connections among brain regions as a factor in reading disorder. Measures from DTI changed in poor readers who improved their reading skills after intense remediation. DTI documents injury to white matter tracts after prematurity. Measures indicative of white matter injury are associated with motor and cognitive impairment in children born prematurely. Further research on DTI is necessary before it can become a routine clinical procedure.