Molecular mechanisms of tumour development in glioblastoma: an emerging role for the circadian clock.

Glioblastoma is one of the most lethal cancers with current therapeutic options lacking major successes. This underlines the necessity to understand glioblastoma biology on other levels and use these learnings for the development of new therapeutic concepts. Mounting evidence in the field of circadian medicine points to a tight interplay between disturbances of the circadian system and glioblastoma progression.

Identifying potential predictable indicators for the management of tertiary hospitals.

Background: The European University Hospitals Alliance (EUHA) recognises the need to move from the classical approach of measuring key performance indicators (KPIs) to an anticipative approach based on predictable indicators to take decisions (Key Decision Indicators, KDIs). It might help managers to anticipate poor results before they occur to prevent or correct them early.

Objective: This paper aims to identify potential KDIs and to prioritize those most relevant for high complexity hospitals.

Reduced expression and activity of patient-derived SHIP1 phosphatase domain mutants.

The characterization of dysregulated proteins in cell signaling pathways is important for the development of therapeutic approaches. The PI3K/AKT/mTOR pathway is frequently upregulated in cancer cells and the SH2-containing inositol 5-phosphatase SHIP1 can act as a negative regulator of the PI3K/AKT pathway. In this study, we investigated different patient-derived mutations within the conserved phosphatase domain of SHIP1.

Developmental Differences in Left Ventricular Strain in IUGR vs. Control Children the First Three Months of Life.

Background: Intrauterine growth restriction (IUGR) may directly affect cardiovascular function in early life. Longitudinal data on left ventricular longitudinal strain (LVLS), a key measure of cardiac function independent of body size, is not available. We hypothesize impaired cardiac function among IUGR newborns and persistence of the impairment until age 3 months.

Preterm birth and infant diurnal cortisol regulation.

Background: Hypothalamic-pituitary-adrenal (HPA) axis adaptation is a potential mechanism linking early life exposures with later adverse health. This study tested the hypothesis that preterm birth is associated with adaptation of diurnal cortisol regulation across infancy.

Methods: A secondary analysis was conducted of saliva cortisol measured morning, midday and evening, monthly, across infancy, as part of a birth cohort conducted in Linköping, Sweden.

Saliva cortisol diurnal variation and stress responses in term and preterm infants.

Objective: To determine if preterm birth is associated with adaptation of the hypothalamic-pituitary-adrenal (HPA) axis and whether HPA axis programming relates to the degree of prematurity (defined as extremely preterm birth at <28 weeks or very preterm birth at 28-32 weeks gestation).

Design: This study reports findings from a prospective birth cohort. Saliva cortisol concentrations were measured prevaccination and postvaccination, and in the morning and evening, at 4 months chronological age.

AKT1 and PTEN show the highest affinities among phosphoinositide binding proteins for the second messengers PtdIns(3,4,5)P and PtdIns(3,4)P.

The phosphoinositides phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P] and phosphatidylinositol-3,4-bisphosphate [PtdIns(3,4)P] function as second messengers and have been implicated in cancerogenesis. The signalling events downstream of PtdIns(3,4,5)P and PtdIns(3,4)P are mediated through a complex network of phosphoinositide binding effector proteins and phosphatases. In this study, we compared the phosphoinositide effector proteins AKT1, TAPP1, TAPP2, VAV1 and P-REX1 and the phosphoinositide phosphatases PTEN, SHIP1 and INPP4B for their binding affinities to PtdIns(3,4,5)P and/or PtdIns(3,4)P using Surface Plasmon Resonance.

Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia.

Current therapeutic approaches for chronic lymphocytic leukemia (CLL) focus on the suppression of oncogenic kinase signaling. Here, we test the hypothesis that targeted hyperactivation of the phosphatidylinositol-3-phosphate/AKT (PI3K/AKT)-signaling pathway may be leveraged to trigger CLL cell death. Though counterintuitive, our data show that genetic hyperactivation of PI3K/AKT-signaling or blocking the activity of the inhibitory phosphatase SH2-containing-inositol-5'-phosphatase-1 (SHIP1) induces acute cell death in CLL cells.

Effect of the p53 P72R Polymorphism on Mutant TP53 Allele Selection in Human Cancer.

Background: TP53 mutations occur in more than 50% of cancers. We sought to determine the effect of the intragenic P72R single nucleotide polymorphism (SNP; rs1042522) on the oncogenic properties of mutant p53.

Methods: P72R allelic selection in tumors was determined from genotype calls and a Gaussian distributed mixture model.

[Follow-up study of very low birthweight children in Sweden at the age of 27-28].

Studies show that very low birthweight can be an important risk factor for mental problems, disturbed fertility and neuroendocrine dysregulation. In a regional long-term study 56 of 86 adult individuals 27 to 28 years of age with a very low birthweight were compared with normal birthweight controls. Analyses of self-reported mental health, socio-demographic factors, sex hormone levels, and hair cortisol levels showed no significant differences between the groups.

The P72R Polymorphism in R248Q/W p53 Mutants Modifies the Mutant Effect on Epithelial to Mesenchymal Transition Phenotype and Cell Invasion via CXCL1 Expression.

High-grade serous carcinoma (HGSC), the most lethal subtype of epithelial ovarian cancer (EOC), is characterized by widespread mutations (>90%), most of which are missense mutations (>70%). The objective of this study was to investigate differential transcriptional targets affected by a common germline P72R SNP () in two p53 hotspot mutants, R248Q and R248W, and identify the mechanism through which the P72R SNP affects the neomorphic properties of these mutants. Using isogenic cell line models, transcriptomic analysis, xenografts, and patient data, we found that the P72R SNP modifies the effect of p53 hotspot mutants on cellular morphology and invasion properties.

Ectopic Expression of Hematopoietic SHIP1 in Human Colorectal Cancer.

Colorectal cancer (CRC) is a heterogeneous disease that results from the accumulation of mutations in colonic mucosa cells. A subclass of CRC is characterized by microsatellite instability, which is thought to occur mainly through inactivation of the DNA mismatch repair genes and . The inositol 5-phosphatase SHIP1 is expressed predominantly in hematopoietic cells.

Characterization of the substrate specificity of the inositol 5-phosphatase SHIP1.

SHIP1 is an inositol 5-phosphatase which is well established for its tumour suppressor potential in leukaemia. Enzymatically, two SHIP1 substrates, PtdIns(3,4,5)P and Ins(1,3,4,5)P have been identified to date. Additional substrates were found for the homologue SHIP2.

Self-reported mental health and cortisol activity at 27-28 years of age in individuals born with very low birthweight.

Aim: To assess mental health outcomes of very low birthweight (VLBW, <1500 g) subjects to adulthood and to examine salivary cortisol and hair cortisol levels and their relation to birth characteristics and mental health.

Methods: A Swedish regional cohort of 56 VLBW subjects and 55 full-term controls were assessed at the ages 27-28 with adult self-reported scales and the mean of 2 days diurnal salivary cortisol and hair cortisol. The cohorts had been assessed at 15 years of age with youth self-reported scales.

Analysis of the FLVR motif of SHIP1 and its importance for the protein stability of SH2 containing signaling proteins.

Binding of proteins with SH2 domains to tyrosine-phosphorylated signaling proteins is a key mechanism for transmission of biological signals within the cell. Characterization of dysregulated proteins in cell signaling pathways is important for the development of therapeutic approaches. The AKT pathway is a frequently upregulated pathway in most cancer cells and the SH2-containing inositol 5-phosphatase SHIP1 is a negative regulator of the AKT pathway.

Women born with very low birth weight have similar menstrual cycle pattern, pregnancy rates and hormone profiles compared with women born at term.

Background: Individuals born very preterm or with very low birth weight (VLBW) have a reduced likelihood to reproduce according to population-based register studies. Extremely low-birth weight born adults had a lower reproduction rate for both men and women in a follow-up study.

Aim: To investigate if being born with VLBW is associated with differences in the reproductive health, i.

Nuclear accumulation of SHIP1 mutants derived from AML patients leads to increased proliferation of leukemic cells.

The inositol 5-phosphatase SHIP1 acts as negative regulator of intracellular signaling in myeloid cells and is a tumor suppressor in myeloid leukemogenesis. After relocalization from the cytoplasm to the plasma membrane SHIP1 terminates PI3-kinase mediated signaling processes. Furthermore, SHIP1 is also found in distinct puncta in the cell nucleus and nuclear SHIP1 has a pro-proliferative function.

Children with a very low birthweight showed poorer reading skills at eight years of age but caught up in most areas by the age of 10.

Aim: We evaluated the development of reading skills in very low birthweight (VLBW) children and controls at 8-10 years of age.

Methods: This study was part of a longitudinal study of VLBW infants born between January 1998 and December 1999 in Sweden. We recruited 49 VLBW children and 44 sex and age-matched full-term controls when they started school at the age of seven and tested them using identical methods for decoding, rapid naming ability, reading comprehension, and spelling and cognitive skills at about eight and 10 years of age.

Neuroimaging of decoding and language comprehension in young very low birth weight (VLBW) adolescents: Indications for compensatory mechanisms.

In preterm children with very low birth weight (VLBW ≤ 1500 g), reading problems are often observed. Reading comprehension is dependent on word decoding and language comprehension. We investigated neural activation-within brain regions important for reading-related to components of reading comprehension in young VLBW adolescents in direct comparison to normal birth weight (NBW) term-born peers, with the use of functional magnetic resonance imaging (fMRI).

Development of salivary cortisol circadian rhythm in preterm infants.

Objectives: To investigate at what age preterm infants develop a salivary cortisol circadian rhythm and identify whether it is dependent on gestational age and/or postnatal age. To evaluate whether salivary cortisol circadian rhythm development is related to behavioral regularity. To elucidate salivary cortisol levels in preterm infants during the first year of life.

Feeling 'too fat' rather than being 'too fat' increases unhealthy eating habits among adolescents - even in boys.

Background: Adolescence is a period of gender-specific physical changes, during which eating habits develop. To better understand what factors determine unhealthy eating habits such as dieting to lose weight, skipping meals, and consumption of unhealthy foods, we studied how physical measurements and body perception relate to eating habits in boys and girls, before and during adolescence.

Methods: For this cross-sectional study, we obtained data from both written questionnaires and physical measurements of height, weight, and waist circumference (WC).

Reading deficits in very low birthweight children are associated with vocabulary and attention issues at the age of seven.

Aim: This Swedish study compared reading skills between seven-year-old children with a very low birthweight (VLBW) and controls with a normal birthweight, exploring associations between reading variables and cognition, parent-rated behaviour, perinatal factors and family factors.

Methods: We studied 51 VLBW children, with no major neurodevelopmental impairments and attending their first year at a regular school, and compared them with the 51 sex- and age-matched controls. The test battery, carried out at 7.

Development of Salivary Cortisol Circadian Rhythm and Reference Intervals in Full-Term Infants.

Background: Cortisol concentrations in plasma display a circadian rhythm in adults and children older than one year. Earlier studies report divergent results regarding when cortisol circadian rhythm is established. The present study aims to investigate at what age infants develop a circadian rhythm, as well as the possible influences of behavioral regularity and daily life trauma on when the rhythm is established.

Behaviour problems and cortisol levels in very-low-birth-weight children.

Abstract Background. There are still diverging results concerning the behaviour of children with very-low-birth-weight (VLBW) and they have been questioned to display different levels of stress hormone than normal-birth-weight (NBW) children. Aims.