Genome-wide DNA methylation profiles in progression to in situ and invasive carcinoma of the breast with impact on gene transcription and prognosis

Background

Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development.

Results

We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma.

Conclusions

This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-014-0435-x) contains supplementary material, which is available to authorized users.     

Chemoattractant axon guidance cues regulate de novo axon trajectories in the embryonic forebrain of zebrafish

The development of axon tracts in the early vertebrate brain is controlled by combinations of soluble, membrane-bound and extracellular matrix molecules. How these multiple and sometimes conflicting guidance cues are integrated in order to establish stereotypical pathways remains to be determined. We show here that when interactions between the chemoattractive signal Netrin1a and its receptor Dcc are suppressed using a loss-of-function approach, a novel axon trajectory emerges in the dorsal diencephalon. Axons arising from a subpopulation of telencephalic neurons failed to project rostrally into the anterior commissure in the absence of either Netrin1a or Dcc. Instead these axons inappropriately exited the telencephalon and ectopically coursed caudally into virgin neuroepithelium. This response was highly specific since loss-of-function of Netrin1b, a paralogue of Netrin1a, generated a distinct phenotype in the rostral brain. These results show that a subpopulation of telencephalic neurons, when freed from long-range chemoattraction mediated by Netrin1a-Dcc interactions, follow alternative instructive cues that lead to creation of an ectopic axon bundle in the diencephalon. This work provides insight into how integration of multiple guidance signals defines the initial scaffold of axon tracts in the embryonic vertebrate forebrain.     

Brief cognitive behavioral therapy compared to general practitioners care for depression in primary care: a randomized trial

Background

Previous studies of acupuncture show favourable results for both subjective and objective outcomes of dry eye. However, firm conclusions could not be drawn from these studies because the quality of the trials was too low to establish concrete evidence. Therefore, this study was designed both to avoid the flaws of the existing trials and to assess the effectiveness, cost-effectiveness and qualitative characteristics of acupuncture treatment for dry eye.

Methods/design

One hundred fifty participants with dry eye will be recruited into three independent hospitals from different areas: Korea Institute of Oriental Medicine, DongGuk University Ilsan Oriental Hospital and Dongshin University Gwangju Oriental Hospital. The number of participants required was calculated from the data of a previous, relevant study. These patients will be randomly allocated into acupuncture treatment or artificial tear groups. Either 17 acupuncture points (bilateral BL2, GB14, TE 23, Ex1, ST1, GB20, LI4, LI11 and single GV23) will be used 3 times a week or disposable artificial tear drops (Refresh Plus^®, ALLERGAN) will be provided for use at least once a day for 4 weeks. The ocular surface disease index (OSDI), tear film break-up time (TFBUT), Schirmer I test, visual analogue scale (VAS) for self-assessment of ocular discomfort, general assessment (by both acupuncture practitioners and participants) and quality of life (QOL) through the Measure Yourself Medical Outcome Profile-2 (MYMOP-2) will be assessed for approximately 3-months for each study participant. In addition, qualitative study and cost-effectiveness of acupuncture treatment will be conducted.

Trial registration

ClinicalTrials.gov (Identifier: NCT01105221).     

Deciphering microbial landscapes of fish eggs to mitigate emerging diseases

Animals and plants are increasingly suffering from diseases caused by fungi and oomycetes. These emerging pathogens are now recognized as a global threat to biodiversity and food security. Among oomycetes, Saprolegnia species cause significant declines in fish and amphibian populations. Fish eggs have an immature adaptive immune system and depend on nonspecific innate defences to ward off pathogens. Here, meta-taxonomic analyses revealed that Atlantic salmon eggs are home to diverse fungal, oomycete and bacterial communities. Although virulent Saprolegnia isolates were found in all salmon egg samples, a low incidence of Saprolegniosis was strongly correlated with a high richness and abundance of specific commensal Actinobacteria, with the genus Frondihabitans (Microbacteriaceae) effectively inhibiting attachment of Saprolegniato salmon eggs. These results highlight that fundamental insights into microbial landscapes of fish eggs may provide new sustainable means to mitigate emerging diseases.     

PRegnancy Outcomes after a Maternity Intervention for Stressful EmotionS (PROMISES): study protocol for a randomised controlled trial

Background

There is ample evidence from observational prospective studies that maternal depression or anxiety during pregnancy is a risk factor for adverse psychosocial outcomes in the offspring. However, to date no previous study has demonstrated that treatment of depressive or anxious symptoms in pregnancy actually could prevent psychosocial problems in children. Preventing psychosocial problems in children will eventually bring down the huge public health burden of mental disease. The main objective of this study is to assess the effects of cognitive behavioural therapy in pregnant women with symptoms of anxiety or depression on the child's development as well as behavioural and emotional problems. In addition, we aim to study its effects on the child's development, maternal mental health, and neonatal outcomes, as well as the cost-effectiveness of cognitive behavioural therapy relative to usual care.

Methods/design

We will include 300 women with at least moderate levels of anxiety or depression at the end of the first trimester of pregnancy. By including 300 women we will be able to demonstrate effect sizes of 0.35 or over on the total problems scale of the child behavioural checklist 1.5-5 with alpha 5% and power (1-beta) 80%.Women in the intervention arm are offered 10-14 individual cognitive behavioural therapy sessions, 6-10 sessions during pregnancy and 4-8 sessions after delivery (once a week). Women in the control group receive care as usual.Primary outcome is behavioural/emotional problems at 1.5 years of age as assessed by the total problems scale of the child behaviour checklist 1.5 - 5 years.Secondary outcomes will be mental, psychomotor and behavioural development of the child at age 18 months according to the Bayley scales, maternal anxiety and depression during pregnancy and postpartum, and neonatal outcomes such as birth weight, gestational age and Apgar score, health care consumption and general health status (economic evaluation).

Trial Registration

Netherlands Trial Register (NTR): NTR2242

     

Besprechungen

Ohne Zusammenfassung     

Physiological neutrophil sequestration in the lung: visual evidence for localization in capillaries

Although the lung is known to be a major site of neutrophil margination, the anatomic location of these sequestered cells within the lung is controversial. To determine the site of margination and the kinetics of neutrophil transit through the pulmonary microvasculature, we infused fluorescein isothiocyanate-labeled canine neutrophils into the pulmonary arteries of 10 anesthetized normal dogs and made fluorescence videomicroscopic observations of the subpleural pulmonary microcirculation through a window inserted into the chest wall. The site of fluorescent neutrophil sequestration was exclusively in the pulmonary capillaries with a total of 951 labeled cells impeded in the capillary bed for a minimum of 2 s. No cells were delayed in the arterioles or venules. Transit times of individual neutrophils varied over a wide range from less than 2 s to greater than 20 min with an exponential distribution skewed toward rapid transit times. These observations indicate that neutrophil margination occurs in the pulmonary capillaries with neutrophils impeded for variable periods of time on each pass through the lung. The resulting wide distribution of transit times may determine the dynamic equilibrium between circulating and marginated neutrophils.     

Differences in trabecular bone of leptin-deficient ob/ob mice in response to biomechanical loading

Objective: It is known that bone mineral density (BMD) and the strength of bone is predicted by body mass. Fat mass is a significant predictor of bone mineral density which correlates with body weight. This suggests that body fat regulates bone metabolism first by means of hormonal factors and second that the effects of muscle and loading are signaling factors in mechanotransduction. Leptin, a peptide hormone produced predominantly by white fat cells, is one of these hormonal factors. The aim of this study was to investigate and measure by micro-CT the different effects of weight-bearing on trabecular bone formation in mice without the stimulation of leptin.