Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

Background Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs.Methods Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [{"type":"clinical-trial","attrs":{"text":"NCT02428842","term_id":"NCT02428842"}}NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed.Results Episomal HPV was much less frequent in CC as compared to anal carcinoma (p < 0.0001). We identified >300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p < 0.0001); HPV18 and HPV45 being always integrated. High HPV copy number was associated with longer PFS (p = 0.011).Conclusions This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.Subject terms: Oncology, Molecular medicine, Biomarkers, Molecular biology     

New insights into a spectrum of developmental malformations related to mTOR dysregulations: challenges and perspectives

In recent years the role of the mammalian target of rapamycin (mTOR) pathway has emerged as crucial for normal cortical development. Therefore, it is not surprising that aberrant activation of mTOR is associated with developmental malformations and epileptogenesis. A broad spectrum of malformations of cortical development, such as focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC), have been linked to either germline or somatic mutations in mTOR pathway‐related genes, commonly summarised under the umbrella term ‘mTORopathies’. However, there are still a number of unanswered questions regarding the involvement of mTOR in the pathophysiology of these abnormalities. Therefore, a monogenetic disease, such as TSC, can be more easily applied as a model to study the mechanisms of epileptogenesis and identify potential new targets of therapy. Developmental neuropathology and genetics demonstrate that FCD IIb and hemimegalencephaly are the same diseases. Constitutive activation of mTOR signalling represents a shared pathogenic mechanism in a group of developmental malformations that have histopathological and clinical features in common, such as epilepsy, autism and other comorbidities. We seek to understand the effect of mTOR dysregulation in a developing cortex with the propensity to generate seizures as well as the aftermath of the surrounding environment, including the white matter.     

Twelve‐month prevalence,comorbidity and correlates of mental disorders in Germany: the Mental Health Module of the German Health Interview and Examination Survey for Adults (DEGS1‐MH)

This paper provides up to date prevalence estimates of mental disorders in Germany derived from a national survey (German Health Interview and Examination Survey for Adults, Mental Health Module [DEGS1‐MH]). A nationally representative sample (N = 5318) of the adult (18–79) population was examined by clinically trained interviewers with a modified version of the Composite International Diagnostic Interview (DEGS‐CIDI) to assess symptoms, syndromes and diagnoses according to DSM‐IV‐TR (25 diagnoses covered). Of the participants 27.7% met criteria for at least one mental disorder during the past 12 months, among them 44% with more than one disorder and 22% with three or more diagnoses. Most frequent were anxiety (15.3%), mood (9.3%) and substance use disorders (5.7%). Overall rates for mental disorders were substantially higher in women (33% versus 22% in men), younger age group (18–34: 37% versus 20% in age group 65–79), when living without a partner (37% versus 26% with partnership) or with low (38%) versus high socio‐economic status (22%). High degree of urbanization (> 500,000 inhabitants versus < 20,000) was associated with elevated rates of psychotic (5.2% versus 2.5%) and mood disorders (13.9% versus 7.8%). The findings confirm that almost one third of the general population is affected by mental disorders and inform about subsets in the population who are particularly affected. Copyright © 2014 John Wiley & Sons, Ltd.     

Multimodal imaging for detecting metamorphopsia after successful retinal detachment repair

Graefe's Archive for Clinical and Experimental Ophthalmology - To investigate the etiologies of metamorphopsia after successful retinal detachment repair. In this retrospective study, we...     

Physical activity and movement skills proficiency of young Filipino children

Recent reports indicate an increasing prevalence of overweight among Filipino children. Considering the known association of physical activity (PA) with obesity, this study reports the findings of an objective monitoring of PA in a sample of Filipino children. The study also explores the relationship of PA with fundamental movement skills (FMS) proficiency. Thirty‐two children (6.54 ± 2.45 years old) wore an accelerometer for 7 days of PA monitoring and were assessed on five FMS (throw, catch, kick, run, jump). The children met the World Health Organization's recommendation of 60 min of PA per day, with more active time being accrued during weekdays than weekends. Children with greater FMS proficiency were found to spend more time in PA than those who were less skillful during weekends. Further research is recommended to examine PA and FMS proficiency associations, exploring the role of social interactions on weekends and weekdays.