Aguirremiller9789

Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated.

A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case-control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions.

In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11-1.41 for breast cancer, and 1.23; 95% CI, 1.07-1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25-1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (

< 0.0001 and

= 0.0005, respectively) two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome.

The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples.

We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.

We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here we aimed to investigate the role of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer (GC) tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of gastric cancer patients and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated GC cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyper-activation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease.

Diagnosing heart failure (HF) is difficult, relying on medical history, symptoms, and signs only. Clinical guidelines recommend natriuretic peptides (NPs) as an additional diagnostic test, notably to exclude HF in suspected patients. NP testing has been available since 2003 for primary care in the Netherlands, but little is known about its uptake.

To evaluate the trend in ordering and appropriateness of NP testing in primary care.

An observational study was performed between January 2005 and December 2013. find more Nine Dutch general practices participated, with 21 000 registered people (approximately 4300 aged ≥65 years).

The total number of patients undergoing NP testing each year was calculated per 1000 patient years (PY) based on the total practice population. NP levels were used to assess whether NP testing was applied to exclude or confirm HF.

The number of NP testing increased from 2.5 per 1000 PY in 2005 to 14.0 per 1000 PY in 2013, with a peak in 2009 of 15.6 per 1000 PY. The proportion of participants with N-terminal B-type natriuretic peptide (NTproBNP) below 125 pg/ml (the exclusionary threshold recommended by the European Society of Cardiology [ESC] guidelines on HF) was on average 30%, and highest in the first year (47%).

After a rapid uptake of NP testing in primary care from 2005 onwards, the use of it seemed to stabilise after 2009, thus leaving patients who are prone to HF without an optimal diagnostic work-up.

After a rapid uptake of NP testing in primary care from 2005 onwards, the use of it seemed to stabilise after 2009, thus leaving patients who are prone to HF without an optimal diagnostic work-up.

Surgical site infections following caesarean section are associated with significant morbidity. Vaginal preparation is the cleansing of the vaginal epithelium with an antibacterial solution to reduce the bacterial load and therefore reduce ascending genital tract infection. It is recommended by the WHO and a Cochrane review in 2018 concluded that vaginal preparation immediately before caesarean section probably reduces the rates of postoperative endometritis.

To implement vaginal preparation prior to caesarean section at Guy's and St Thomas' Hospital NHS Foundation Trust and reduce rates of deep surgical site infections.

The protocol (included within the appendices) for vaginal preparation prior to caesarean section was developed after reviewing the available evidence. Two vaginal preparation champions, a midwife and a scrub nurse, were selected to help promote and assist in the implementation. The first implementation cycle included elective and category II and III caesarean sections. To ensure acceptato success.

Vaginal preparation prior to caesarean section has been successfully implemented at Guy's and St Thomas' Hospital NHS Foundation Trust. This simple, cheap intervention, performed with readily available materials, is still being performed in a high number of caesarean sections 12 months post-implementation. It has resulted in a reduction in deep surgical site infections. Involvement of key stakeholders and the recruitment of vaginal preparation champions were key to success.