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Purpose To assess the social cognitive constructs of the Health Action Process Approach (HAPA) of parents of high caries risk children to be treated under intravenous sedation (IVS) or with behavioural guidance techniques (BGT), and to assess the changes in these constructs for each treatment group after treatment. Design In this cohort study, 160 children aged 3–10 years were allocated by their paediatric dentist to either IVS (77.4%) or BGT. Their parents filled out a HAPA questionnaire, before (T1, n  = 160), immediately (T2, n  = 108) and three months (T3, n  = 71) after their children's dental rehabilitation. Results Before treatment, all parents had high scores on all social cognitive constructs. There were no differences in mean HAPA scores between the treatment groups ( p  > 0.05). After treatment, mean scores changed in both groups. In the BGT group, action self-efficacy changed from 3.64 (T1) to 3.36(T2) ( p  = 0.027) and to 3.13 (T3) ( p  = 0.021) and coping self-efficacy changed from 3.63 (T1) to 3.23 (T2) ( p  = 0.015). In the IVS group, action planning changed from 3.25 (T1) to 3.05(T3) ( p  = 0.036) and action control changed from 2.58 (T1) to 2.82 (T2) ( p  = 0.012) and to 2.87 (T3) ( p  = 0.006). Conclusions High scores on social cognitive constructs of parents of children referred to a paediatric dentist showed that they seem to be motivated to brush their children’s teeth, irrespective of the treatment group. Small changes were observed in the HAPA constructs, however, these are not considered clinically relevant.

Introduction Previous studies showed that 5-year-old Dutch-Moroccan children had significantly higher dmft scores compared to Dutch children of the same age, even after correction for socio-economic status. The mechanisms underlying this difference are little understood. Aim To explore cultural factors involved in poorer oral health of Dutch-Moroccan children by identifying knowledge, attitudes and behaviour of their mothers concerning their children’s oral health. Methods In 2012 mothers of Dutch-Moroccan preschool children in two cities in the Netherlands were interviewed in two focus groups (n = 16) or individual semi-structured interviews (n = 13). Semi structured interviews were also c onducted with three oral health professionals, working with Dutch-Moroccan children, and one physician from an under-five-clinic. All interviews were voice recorded, transcribed and inductively coded. MAXQDA software was used for data analysis. Results All mothers mentioned pain complaints, swelling and black front teeth as oral health problems in their children. Although mothers were aware that brushing teeth and reducing sugary snacks are effective preventative strategies, they did not sufficiently implement these measures. This was due to lack of brushing skills, insufficient awareness of the daily sugar intake of their children and their childrearing concerning these measures. Most mothers indicated they felt empowered in making dental care decisions. Conclusions This research revealed the presence of knowledge on preventive strategies regarding their children’s oral health in Dutch-Moroccan mothers, but an inadequate implementation of these measures in their daily lives. Additional qualitative research is needed to gain deeper insight for broader exposure of values, knowledge and culture.

Stroma tissue surrounding cancer cells plays an important role in tumor development and behavior. In colorectal cancer, it has been found that the amount of stroma within the primary tumor is of prognostic value. We therefore have evaluated the prognostic value of this tumor–stroma ratio for breast cancer. A cohort of 574 early breast cancer patients, primarily treated with surgery between 1985 and 1994 was analyzed for the tumor–stroma ratio. The percentage of stroma was visually estimated on Haematoxylin-Eosin (H&E) stained histological sections. Patients with more than 50% intra-tumor stroma were quantified as stroma rich and patients with less than 50% as stroma poor. For the total group of patients, stroma-rich tumors had a shorter relapse-free period (RFP) ( P  = 0.001) and overall survival (OS) ( P  = 0.025) compared to stroma-poor tumors. Tumor–stroma ratio was an independent prognostic parameter for the total group of patients ( P  < 0.001) and also in stratified analysis based on systemic treatment. Importantly, in the triple-negative cancer subpopulation, patients with stroma-rich tumors had a 2.92 times higher risk of relapse ( P  = 0.006) compared to those with stroma-poor tumors, independently of other clinico-pathological parameters. Five-year RFP-rates for triple-negative cancer patients with stroma-rich compared to stroma-poor tumors were 56 and 81%, respectively. Tumor–stroma ratio has proven to be an independent prognostic factor for RFP in breast cancer patients and especially in the triple-negative cancer subpopulation. Tumor–stroma ratio could be easily implemented in routine daily pathology diagnostics, as it is simple to determine, reproducible, and performed in quick time.

Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) and mesenchymal (MES) tumor cell types, which differ in phenotype, super-enhancers (SEs) and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed the ADRN transcriptional landscape towards a MES state. A transcriptional feed-forward circuitry of NOTCH-family transcription factors amplifies the NOTCH signaling levels, explaining the swift transition between two semi-stable cellular states. This transition induces genome-wide remodeling of the H3K27ac landscape and a switch from ADRN SEs to MES SEs. Once established, the NOTCH feed-forward loop maintains the induced MES state. In vivo reprogramming of ADRN cells shows that MES and ADRN cells are equally oncogenic. Our results elucidate a swift transdifferentiation between two semi-stable epigenetic cellular states. Neuroblastoma includes adrenergic and mesenchymal cell types that can interconvert. Here, the authors show that this transdifferentiation is driven by a NOTCH feedforward loop that allows a swift transition between two semi-stable cellular states.

Epithelial mesenchymal transition (EMT) plays an important role in the development of metastases. One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by transcription factors, such as SNAIL, SLUG, and TWIST. We examined the prognostic value of these factors as well as E-cadherin and N-cadherin, in a well-described large cohort of breast cancer patients treated with primary surgery. Analyses were stratified by estrogen receptor (ER) status, because of its crucial role in the regulation of these transcription factors. SNAIL, SLUG, and TWIST expression were examined on a TMA containing 575 breast tumors using immunohistochemistry. Nuclear expression was quantified using a weighted histoscore and classified as high versus low expression, based on the median histoscore. High expression of SNAIL, SLUG, and TWIST was seen in 54, 50, and 50% of tumors, respectively. The level of SNAIL ( P  = 0.014) and TWIST ( P  = 0.006) expression was associated with a worse patient relapse-free period, specifically in patients with ER-positive tumors (interaction Cox proportional hazards P  = 0.039). Combining both factors resulted in an independent prognostic factor with high discriminative power (both low versus either high: HR 1.15; both low versus both high HR 1.84; P  = 0.010). Co-expression of SNAIL–TWIST was associated with low-E-cadherin and high-N-cadherin expression, especially in ER-positive tumors ( P  = 0.009), suggesting that, through interactions with ER, SNAIL and TWIST may regulate E- and N-cadherin expression, thereby inducing EMT. Our results are indicative that SNAIL and TWIST play a crucial role in EMT through regulation of E- and N-cadherin expression, exclusively in ER-positive breast cancer patients.

Long interspersed element 1 (LINE-1), a non-coding genomic repeat sequence, methylation status can influence tumor progression. In this study, the clinical significance of LINE-1 methylation status was assessed in primary breast cancer in young versus old breast cancer patients. LINE-1 methylation index (MI) was assessed by absolute quantitative assessment of methylated alleles (AQAMA) PCR assay. Initially, LINE-1 MI was assessed in a preliminary study of 235 tissues representing different stages of ductal breast cancer development. Next, an independent cohort of 379 primary ductal breast cancer patients (median follow-up 18.9 years) was studied. LINE-1 hypomethylation was shown to occur in DCIS and invasive breast cancer. In primary breast cancer it was associated with pathological tumor stage ( p  = 0.026), lymph node metastasis ( p  = 0.022), and higher age at diagnosis (>55, p  < 0.001). In multivariate analysis, LINE-1 hypomethylation was associated with decreased OS (HR 2.19, 95 % CI 1.17–4.09, log-rank p  = 0.014), DFS (HR 2.05, 95 % CI 1.14–3.67, log-rank p  = 0.016) and increased DR (HR 2.83, 95 % CI 1.53–5.21, log-rank p  = 0.001) in younger (≤55 years), but not older patients (>55 years). LINE-1 analysis of primary breast cancer demonstrated cancer-related age-dependent hypomethylation. In patients ≤55 years, LINE-1 hypomethylation portends a high-risk of DR.

Background Cell surface NKG2D ligands (NKG2DL) bind to the activating NKG2D receptor present on NK cells and subsets of T cells, thus playing a role in initiating an immune response. We examined tumor expression and prognostic effect of NKG2DL in breast cancer patients. Methods Our study population (n = 677) consisted of all breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Formalin-fixed paraffin-embedded tumor tissue was immunohistochemically stained with antibodies directed against MIC-A/MIC-B (MIC-AB), ULBP-1, ULBP-2, ULBP-3, ULBP-4, and ULBP-5. Results NKG2DL were frequently expressed by tumors (MIC-AB, 50% of the cases; ULBP-1, 90%; ULBP-2, 99%; ULBP-3, 100%; ULBP-4, 26%; ULBP-5, 90%) and often showed co-expression: MIC-AB and ULBP-4 (p = 0.043), ULBP-1 and ULBP-5 (p = 0.006), ULBP-4 and ULBP-5 (p < 0.001). MIC-AB (p = 0.001) and ULBP-2 (p = 0.006) expression resulted in a statistically significant longer relapse free period (RFP). Combined expression of these ligands showed to be an independent prognostic parameter for RFP (p < 0.001, HR 0.41). Combined expression of all ligands showed no associations with clinical outcome. Conclusions We demonstrated for the first time that NKG2DL are frequently expressed and often co-expressed in breast cancer. Expression of MIC-AB and ULBP-2 resulted in a statistically significant beneficial outcome concerning RFP with high discriminative power. Combination of all NKG2DL showed no additive or interactive effect of ligands on each other, suggesting that similar and co-operative functioning of all NKG2DL can not be assumed. Our observations suggest that among driving forces in breast cancer outcome are immune activation on one site and tumor immune escape on the other site.

Self-facilitation through ecosystem engineering (i.e., organism modification of the abiotic environment) and consumer-resource interactions are both major determinants of spatial patchiness in ecosystems. However, interactive effects of these two mechanisms on spatial complexity have not been extensively studied. We investigated the mechanisms underlying a spatial mosaic of low-tide exposed hummocks and waterlogged hollows on an intertidal mudflat in the Wadden Sea dominated by the seagrass Zostera noltii. A combination of field measurements, an experiment and a spatially explicit model indicated that the mosaic resulted from localized sediment accretion by seagrass followed by selective waterfowl grazing. Hollows were bare in winter, but were rapidly colonized by seagrass during the growth season. Colonized hollows were heavily grazed by brent geese and widgeon in autumn, converting these patches to a bare state again and disrupting sediment accretion by seagrass. In contrast, hummocks were covered by seagrass throughout the year and were rarely grazed, most likely because the waterfowl were not able to employ their preferred but water requiring feeding strategy ('dabbling') here. Our study exemplifies that interactions between ecosystem engineering by a foundation species (seagrass) and consumption (waterfowl grazing) can increase spatial complexity at the landscape level.

Jan Molenaar and colleagues show that LIN28B is overexpressed and amplified in human neuroblastomas and that LIN28B regulates let-7 family miRNAs and MYCN. They create a transgenic mouse model of LIN28B overexpression and show that these mice develop neuroblastoma tumors. LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo . Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B–let-7–MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives.

Ecosystem productivity commonly increases asymptotically with plant species diversity, and determining the mechanisms responsible for this well-known pattern is essential to predict potential changes in ecosystem productivity with ongoing species loss. Previous studies attributed the asymptotic diversity-productivity pattern to plant competition and differential resource use (e. g., niche complementarity). Using an analytical model and a series of experiments, we demonstrate theoretically and empirically that host-specific soil microbes can be major determinants of the diversity-productivity relationship in grasslands. In the presence of soil microbes, plant disease decreased with increasing diversity, and productivity increased nearly 500%, primarily because of the strong effect of density-dependent disease on productivity at low diversity. Correspondingly, disease was higher in plants grown in conspecific-trained soils than heterospecific-trained soils (demonstrating host-specificity), and productivity increased and host-specific disease decreased with increasing community diversity, suggesting that disease was the primary cause of reduced productivity in speciespoor treatments. In sterilized, microbe-free soils, the increase in productivity with increasing plant species number was markedly lower than the increase measured in the presence of soil microbes, suggesting that niche complementarity was a weaker determinant of the diversityproductivity relationship. Our results demonstrate that soil microbes play an integral role as determinants of the diversity-productivity relationship.