[Methylation of the RASSF1A tumor suppressor gene promoter. Risk factor for carcinogenesis of urological tumors]. / Die Methylierung des RASSF1A-Tumorsuppressorgenpromotors. Risikofaktor für die Karzinogenese urologischer Tumoren.

Molecular targets of known risk factors for the development of urological tumors, such as age, smoking, and adiposity, have not yet been elucidated. Hypermethylation of CpG islands in promoters can lead to silencing of gene expression and has frequently been detected in tumors. Age-dependent accumulation of methylation of gene promoters has been observed in various normal tissues and is discussed as a common risk factor for carcinogenesis.Here we describe the RASSF1A tumor suppressor gene as exhibiting an age-dependent promoter methylation in normal kidney tissue, which is additionally affected by the risk factors of anthracosis and adiposity. Furthermore, we found significantly increased methylation of the RASSF1A promoter when comparing peripheral versus central zone prostatic tissue samples.Preliminary expression analysis indicates that RASSF1A could be involved in early tumorigenesis. Our results support the hypothesis that age and other lifestyle-dependent factors may influence promoter methylation of specific genes, possibly serving as future individual tumor risk markers.

Disentangling the autism-anxiety overlap: fMRI of reward processing in a community-based longitudinal study.

Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age=14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2x2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth.

Erythroplasia of queyrat: coinfection with cutaneous carcinogenic human papillomavirus type 8 and genital papillomaviruses in a carcinoma in situ.

Erythroplasia of Queyrat is a carcinoma in situ that mainly occurs on the glans penis, the prepuce, or the urethral meatus of elderly males. Up to 30% progress to squamous cell carcinoma. The cause of erythroplasia of Queyrat is largely unknown. Human papillomavirus type 16 DNA has previously been detected only in very few distinctly characterized patients. We have investigated 12 paraffin-embedded biopsies from eight patients with penile erythroplasia of Queyrat and control biopsies of inflammatory penile lesions, of genital Bowen's disease, and of premalignant/malignant cervical or vulvar lesions by 10 different polymerase chain reaction protocols for the presence of cutaneous and genital/mucosal human papillomaviruses. Human papillomavirus typing was performed by sequencing (cloned) polymerase chain reaction products. Human papillomavirus DNA was detected in all erythroplasia of Queyrat patients and in none of the controls with inflammatory penile lesions. The rare cutaneous carcinogenic epidermodysplasia verruciformis-associated human papillomavirus type 8 was present in all erythroplasia of Queyrat patients and the genital high-risk human papillomavirus type 16 in seven of eight patients (88%). In addition to human papillomavirus type 8 and human papillomavirus type 16, four patients carried the genital carcinogenic human papillomavirus type 39 and/or type 51. All human papillomavirus type 8 sequences found in erythroplasia of Queyrat showed some polymorphism among each other and differed in specific nucleotide exchanges from the human papillomavirus type 8 reference sequence. Viral load determinations (human papillomavirus copies/beta-globin gene copies) by realtime polymerase chain reactions showed that the human papillomavirus type 16 levels in the erythroplasia of Queyrat biopsies were one to five orders of magnitude higher than the human papillomavirus type 8 levels. Human papillomavirus type 8 was not detected in cervical or vulvar precancerous and cancerous lesions and in Bowen's disease lesions that carried genital human papillomavirus types. The data suggest that in erythroplasia of Queyrat, in contrast to other genital neoplasias, a coinfection with human papillomavirus type 8 and carcinogenic genital human papillomavirus types occurs. The presence or absence of human papillomavirus type 8 might help to distinguish between penile erythroplasia of Queyrat and Bowen's diseases.

Hypotonic swelling or stretch does not change cytosolic calcium in mouse renal juxtaglomerular cells.

This study aimed to examine the influence of cell swelling and of direct mechanical stretch on the cytosolic calcium concentration in mouse renal juxtaglomerular cells. To this end JG cells located in isolated mouse renal afferent arterioles were exposed to hypotonic extracellular fluid to cause cell swelling or were mechanically stretched and cytosolic calcium was monitored with fura-2 calcium microspectrofluorimetry. None of the above mentioned manoeuvres caused an increase of cytosolic calcium in the juxtaglomerular cells, which all responded to ionomycin (5 micrograms mL-1) with a marked calcium mobilization. Exposure of cultured rat renal mesangial cells to hypotonic buffer or direct mechanical stress increased cytosolic calcium in 90% of the cells under investigation. These findings suggest that cell swelling or an increased stretch of the plasma membrane of juxtaglomerular cells located in renal afferent arterioles does not lead to measurable increases of the cytosolic calcium concentration. It appears less likely therefore that a membrane-stretch regulated calcium influx has a major functional role in JG cells.