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Background: MicroRNAs (miRNAs) regulate expression of many cancer-related genes through posttranscriptional repression of their mRNAs. In this study we investigate the proto-oncogene MYCN as a target for miRNA regulation. Methods: A luciferase reporter assay was used to investigate software-predicted miRNA target sites in the 3′-untranslated region (3′UTR) of MYCN . The miRNAs were overexpressed in cell lines by transfection of miRNA mimics or miRNA-expressing plasmids. Mutation of the target sites was used to validate MYCN 3′UTR as a direct target of several miRNAs. To measure miRNA-mediated suppression of endogenous N-myc protein, inhibition of proliferation and inhibition of clonogenic growth, miRNAs were overexpressed in a MYCN -amplified neuroblastoma cell line. Results: The results from this study show that MYCN is targeted by several miRNAs. In addition to the previously shown mir-34a/c , we experimentally validate mir-449 , mir-19a/b , mir-29a/b/c, mir-101 and let-7e/mir-202 as direct MYCN -targeting miRNAs. These miRNAs were able to suppress endogenous N-myc protein in a MYCN -amplified neuroblastoma cell line. The let-7e and mir-202 were strong negative regulators of MYCN expression. The mir-101 and the let-7 family miRNAs let-7e and mir-202 inhibited proliferation and clonogenic growth when overexpressed in Kelly cells. Conclusion: The tumour-suppressor miRNAs let-7 and mir-101 target MYCN and inhibit proliferation and clonogenic growth of MYCN -amplified neuroblastoma cells.

Nasal colonisation with Staphylococcus aureus is a risk factor for developing nosocomial infections. It has been reported that S. epidermidis may produce a serine protease (Esp) inhibiting S. aureus biofilm formation and nasal colonisation. We aimed to analyse the correlation between S. aureus nasal and/or throat carriage and co-colonisation with S. epidermidis strains carrying esp , and the inhibitory effects of S. epidermidis culture supernatants on S. aureus biofilm formation and growth. We obtained 114  S. epidermidis isolates from the nose and 74  S. aureus from the nose and/or throat of healthy adolescents. S. aureus biofilm formation was analysed in a microtitre plate assay and the prevalence of ica , encoding biofilm formation, and esp was analysed with polymerase chain reaction (PCR). Inhibitory effects of S. epidermidis culture supernatants on S. aureus biofilm formation and growth was analysed in vitro. esp prevalence and expression was correlated with inhibitory effects. We detected biofilm formation in 45/74 (61 %) S. aureus strains. The ica operon was more prevalent in isolates colonising the nose (12/15; 80 %) versus isolates colonising the throat only (8/46; 17 %). Almost two-thirds of S. epidermidis culture supernatants displayed high (≥50 %) S. aureus biofilm inhibitory activity, without affecting growth. We found no correlation between the level of inhibitory activity and S. aureus colonisation. esp was ubiquitous in S. epidermidis , but esp expression did not correlate with biofilm inhibitory activity. S. epidermidis culture supernatants inhibit S. aureus biofilm formation, but do not affect bacterial growth. esp expression was not correlated with the inhibitory effects observed.

Objective To compare a comprehensive lifestyle intervention for overweight children performed in groups of families with a conventional single-family treatment. Two-year follow-up data on anthropometric and psychological outcome are presented. Design Overweight and obese children aged 6–12 years with body mass index (BMI) corresponding to ≥27.5 kg/m2 in adults were randomised to multiple-family (n=48) or single-family intervention (n=49) in a parallel design. Multiple-family intervention comprised an inpatient programme with other families and a multidisciplinary team, follow-up visits in their hometown, weekly physical activity and a family camp. Single-family intervention included counselling by paediatric nurse, paediatric consultant and nutritionist at the hospital and follow-up by a community public health nurse. Primary outcome measures were change in BMI kg/m2 and BMI SD score after 2 years. Results BMI increased by 1.29 kg/m2 in the multiple-family intervention compared with 2.02 kg/m2 in the single-family intervention (p=0.075). BMI SD score decreased by 0.20 units in the multiple-family group and 0.08 units in the single-family intervention group (p=0.046). A between-group difference of 2.4 cm in waist circumference (p=0.038) was detected. Pooled data from both treatment groups showed a significant decrease in BMI SD score of 0.14 units and a significant decrease in parent-reported and self-reported Strength and Difficulty Questionnaire total score of 1.9 units. Conclusions Two-year outcome showed no between-group difference in BMI. A small between-group effect in BMI SD score and waist circumference favouring multiple-family intervention was detected. Pooled data showed an overall improvement in psychological outcome measures and BMI SD score. Trial registration number NCT00872807, http://www.clinicaltrials.gov.

Abnormal increases in nucleolar size and number caused by dysregulation of ribosome biogenesis has emerged as a hallmark in the majority of spontaneous cancers. The observed ribosome hyperactivity can be directly induced by the MYC transcription factors controlling the expression of RNA and protein components of the ribosome. Neuroblastoma, a highly malignant childhood tumor of the sympathetic nervous system, is frequently characterized by MYCN gene amplification and high expression of MYCN and c-MYC signature genes. Here, we show a strong correlation between high-risk disease, MYCN expression, poor survival, and ribosome biogenesis in neuroblastoma patients. Treatment of neuroblastoma cells with quarfloxin or CX-5461, two small molecule inhibitors of RNA polymerase I, suppressed MycN expression, induced DNA damage, and activated p53 followed by cell cycle arrest or apoptosis. CX-5461 repressed the growth of established MYCN -amplified neuroblastoma xenograft tumors in nude mice. These findings suggest that inhibition of ribosome biogenesis represent new therapeutic opportunities for children with high-risk neuroblastomas expressing high levels of Myc.

BackgroundNeuroblastoma is a neoplasm of the sympathetic nervous system representing the most frequently diagnosed solid tumour in infants. Despite continued improvements in cancer treatment, the overall survival of patients with high risk neuroblastoma is still only 40–50%. Irrespective of risk factors, neuroblastomas generally respond well to initial therapy. However, the majority of high risk patients relapse with tumours refractory to standard chemotherapeutic agents. Therefore, the understanding of biological and molecular aspects of drug resistance in neuroblastoma may provide new opportunities for therapy of aggressive neuroblastoma.Recent evidence has revealed a substantial role of microRNAs (miRNAs) in multidrug resistance in various cancer types. MicroRNAs are small (18–24 nucleotides) non-coding RNA molecules that regulate the expression of genes at the post-transcriptional level by either direct cleavage of target mRNAs or repression of translation. Several studies indicate that deviant expression of certain miRNAs correlate with poor clinical outcome in neuroblastoma. However, the role of miRNAs in neuroblastoma cell resistance to chemotherapeutic drugs is poorly understood.MethodsTo explore the role of miRNAs in the resistance of neuroblastoma cells to anticancer drugs, we generated miRNA cDNA libraries from six isogenic human neuroblastoma cell line pairs established from the same patients at the time of initial diagnosis and relapse following therapy. To analyse expression patterns of miRNAs, a deep sequencing analysis (SOLiD sequencing) was performed using the miRNA cDNA libraries.ResultsDeep sequencing analysis (SOLiD sequencing) revealed differential expression patterns of miRNAs before and after treatment. Systematic analysis of these miRNA expression patterns identified potential alterations in pathways associated with drug resistance suggesting that dysregulation of miRNAs might influence sensitivity to therapy.ConclusionWe anticipate that our findings will provide new insights into the molecular mechanisms of drug resistance in neuroblastoma.

Objective To compare a new comprehensive lifestyle programme performed in groups of families with overweight (included obese) children with a more conventional single-family programme. The study design and interim anthropometrical results after 12 months are presented. Design Altogether 97 overweight and obese children aged 6–12 years with body mass index (BMI) corresponding to cut-off point ≥27.5 in adults were included. Study participants were randomised to multiple-family intervention (MUFI) or single-family intervention (SIFI) in a parallel design. MUFI comprised a 3-day inpatient programme at the hospital with other families and a multidisciplinary team, follow-up visits in their hometown individually and in groups, organised physical activity twice weekly and a 4-day family camp after 6 months. SIFI comprised individual counselling by paediatric nurse, paediatric consultant and nutritionist at the hospital and follow-up by public health nurse in the community. Solution focused approach was applied in both interventions. Primary outcome measures were change in BMI kg/m2 and BMI SD score (BMI SDS). Results BMI increased by 0.37 units in the MUFI compared to 0.77 units in the SIFI (p=0.18). BMI SDS decreased by 0.16 units in the MUFI group compared to 0.07 units in the SIFI group (p=0.07). Secondary endpoint waist circumference decreased 0.94 cm in the multiple-family group and increased 0.95 cm in the single-family group, p=0.04. Conclusions Interim analysis after 12 months showed no between-group difference in terms of BMI or BMI SDS. The MUFI group had a significant decrease in waist circumference compared to the SIFI group. The trial is registered at http://www.clinicaltrials.gov (NCT00872807)

Prolonged stress is a risk factor for developing mental illness and stress-related diseases. As there has been an increase in self-reported psychological symptoms and diagnosis of mental illness among Scandinavian adolescents, more knowledge of stress prevalence in this age group is needed. This literature review will investigate a possible increase in stress prevalence among Scandinavian adolescents, aged 13-18, between the years 2000 and 2019. A systematic literature search was conducted in the PubMed and PsycInfo databases. In addition, a grey literature search was conducted to find relevant surveys and reports. Altogether, nine papers and nine surveys, and reports containing relevant data were identified, assessed for risk of bias, and included in the analysis. The results show higher stress scores among the older participants in the age group 13-18 years and a gender difference, where girls score higher than boys. The literature neither supports nor rejects the hypothesis that stress levels have increased among adolescents in Scandinavia, from year 2000 to 2019. Only two of the included studies used a validated stress questionnaire and there was a substantial risk of non-response bias. Therefore, the existing literature is considered insufficient to determine if there has been an increase in stress over time. A majority of the papers, surveys, and reports had moderate risk of bias. Further research using validated stress questionnaires in representative populations is needed to investigate changes in stress prevalence among Scandinavian adolescents. Also, the age and gender difference in stress prevalence among 13-18-year-olds may be of relevance for planning preventive interventions to reduce stress.

Ex vivo drug response profiling is emerging as a valuable tool for identifying drug resistance mechanisms and advancing precision medicine in hematological cancers. However, the functional impact of dysregulation of the epigenome and transcriptome in this context remains poorly understood. In this study, we combined ex vivo drug sensitivity profiling with transcriptomic and epigenomic analyses in diagnostic samples from 597 pediatric B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) patients. Ex vivo resistance to antimetabolites (e.g., cytarabine, thioguanine), glucocorticoids (e.g., dexamethasone, prednisolone), and doxorubicin was independently associated with reduced relapse‐free survival (P < 0.05). Molecular profiling identified pretreatment DNA methylation and gene expression patterns distinguishing resistant from sensitive cases, revealing key drug resistance signatures. These included aberrant expression of genes related to heme metabolism (e.g., ATPV06A) and KRAS signaling (e.g., GS02). Notably, we also observed atypical expression of genes usually restricted to T cells and other immune cells (e.g., ITK) in resistant BCP‐ALL cells. Our findings demonstrate that ex vivo drug response patterns are predictive of clinical outcomes and reflect intrinsic molecular states associated with drug tolerance. This integrative multi‐omics approach highlights potential therapeutic targets and underscores the value of functional precision medicine in identifying treatment vulnerabilities in pediatric ALL.

The MYCN oncogene is frequently amplified in neuroblastoma and is associated with aggressive disease and treatment failure. MYCN induces expression of different miRNAs, which are posttranscriptional regulators of gene expression with established roles in neuroblastoma development.In this study, we show that MYCN -amplified cell lines not only express miRNAs with functions inside the cell, but also secrete populations of miRNAs inside small vesicular structures called exosomes, with the ability to shuttle to other cells. We have isolated and characterised exosomes from MYCN amplified cell lines, and here demonstrate their ability to be taken up by other cells. By profiling the miRNA expression, we demonstrate high expression of a group of established on comirs in exosomes from two MYCN- amplified cell lines. Despite the fact that other studies have demonstrated the ability of exosomal miRNAs to regulate their targets in recipient cells, we did not observe this with exosomes from MYCN -amplified cells. However, exosomes were able to induce in vitro angiogenic tube formation, suggesting that they can have tumorigenic properties.These new findings reveal a potential new way for MYCN -amplified neuroblastoma cells to interact with their environment.

Relapse remains the main obstacle to curing childhood acute lymphoblastic leukemia (ALL). The aims of this study were to compare incidence of relapse, prognostic factors, and survival after relapse between three consecutive Nordic Society of Pediatric Hematology and Oncology trials. Relapse occurred as a primary event in 638 of 4 458 children (1.0–14.9 years) diagnosed with Ph-negative ALL between 1992 and 2018. The 5-year cumulative incidence of relapse was 17.3% (95% CI 15.4–19.2%) and 16.5% (95% CI 14.3–18.8%) for patients in the ALL1992 and ALL2000 trials, respectively, but decreased to 8.4% (95% CI 7.0–10.1%) for patients in the ALL2008 trial. No changes in duration of first complete remission and site of relapse were observed over time; however, high hyperdiploidy, and t(12;21) decreased in the ALL2008 trial. The 4-year overall survival after relapse was 56.6% (95% CI 52.5–60.5%) and no statistically significant temporal improvements were observed. Age ≥10 years, T-cell immunophenotype, bone-marrow involvement, early and very early relapse, hypodiploidy, and Down syndrome all independently predicted worse outcome after relapse. Improvements in the primary treatment of childhood ALL has resulted in fewer relapses. However, failure to improve outcome of remaining relapses suggests a selection of harder-to-cure relapses and calls for new therapeutic strategies.