Correlation of SHOX2 Gene Amplification and DNA Methylation in Lung Cancer Tumors

<p>Abstract</p> <p>Background</p> <p>DNA methylation in the <it>SHOX2 </it>locus was previously used to reliably detect lung cancer in a group of critical controls, including 'cytologically negative' samples with no visible tumor cell content, at a high specificity based on the analysis of bronchial lavage samples. This study aimed to investigate, if the methylation correlates with <it>SHOX2 </it>gene expression and/or copy number alterations. An amplification of the <it>SHOX2 </it>gene locus together with the observed tumor-specific hypermethylation might explain the good performance of this marker in bronchial lavage samples.</p> <p>Methods</p> <p><it>SHOX2 </it>expression, gene copy number and DNA methylation were determined in lung tumor tissues and matched morphologically normal adjacent tissues (NAT) from 55 lung cancer patients. Quantitative HeavyMethyl (HM) real-time PCR was used to detect <it>SHOX2 </it>DNA methylation levels. <it>SHOX2 </it>expression was assayed with quantitative real-time PCR, and copy numbers alterations were measured with conventional real-time PCR and array CGH.</p> <p>Results</p> <p>A hypermethylation of the <it>SHOX2 </it>locus in tumor tissue as compared to the matched NAT from the same patient was detected in 96% of tumors from a group of 55 lung cancer patients. This correlated highly significantly with the frequent occurrence of copy number amplification (p < 0.0001), while the expression of the <it>SHOX2 </it>gene showed no difference.</p> <p>Conclusions</p> <p>Frequent gene amplification correlated with hypermethylation of the <it>SHOX2 </it>gene locus. This concerted effect qualifies <it>SHOX2 </it>DNA methylation as a biomarker for lung cancer diagnosis, especially when sensitive detection is needed, i.e. in bronchial lavage or blood samples.</p

Robot-assisted surgery for the management of apical prolapse: a bicentre prospective cohort study

Objective: Robot‐assisted surgery is a recognized treatment for pelvic‐organ prolapse. Many of the surgical subgroup outcomes for apical prolapse are reported together leading to a paucity of homogenous data. Design: Prospective observational cohort study (https://clinicaltrials.gov; identifier NCT01598467) assessing outcomes for homogeneous subgroups of robot‐assisted apical prolapse surgery. Setting: Two European tertiary referral hospitals. Population: Consecutive patients undergoing robot‐assisted sacrocolpopexy (RASC) and supracervical hysterectomy with sacrocervicopexy (RSHS). Methods: Anatomical cure (simplified Pelvic Organ Prolapse Quantification (sPOPQ) stage 1,), subjective cure (symptoms of bulge) and quality of life (Pelvic Floor Impact Questionnaire [PFIQ‐7]). Main Outcome measures: Primary outcome: anatomical and subjective cure. Secondary outcomes: surgical safety and intraoperative variables. Results: Total 305 patients included (RASC N=188, RSHS N=117). Twelve months follow‐up available for 144 (RASC 76.6%) and 109 (RSHS 93.2%). Anatomical success of the apical compartment occurred in 91% (RASC) and in 99% (RSHS). In all compartments, success percentages were 67% and 65% respectively. Most recurrences were anterior compartment (15.7% RASC [symptomatic 12.1%]; 22.9% RSHS [symptomatic 4.8%]). Symptoms of bulge improved from 97.4% to 17.4% (p<0.0005). PFIQ‐7 scores improved from 76.7 ± 62.3 to 13.5 ± 31.1 (p<0.0005). Duration of surgery increased significantly in RSHS (183.1 ± 38.2 versus 145.3 ± 29.8 [p<0.0005]). Intraoperative complications and conversion rates were low (RASC: 5.3% and 4.3%; RSHS: 0.0% and 0.0%). Four severe postoperative complications occurred after RASC (2.1%) and one after RSHS (1.6%). Conclusion: This is the largest reported prospective cohort study on robot‐assisted apical prolapse surgery. Both procedures are safe, with durable results

Cancer Genomics Identifies Regulatory Gene Networks Associated with the Transition from Dysplasia to Advanced Lung Adenocarcinomas Induced by c-Raf-1

Background: Lung cancer is a leading cause of cancer morbidity. To improve an understanding of molecular causes of disease a transgenic mouse model was investigated where targeted expression of the serine threonine kinase c-Raf to respiratory epithelium induced initialy dysplasia and subsequently adenocarcinomas. This enables dissection of genetic events associated with precancerous and cancerous lesions. Methodology/Principal Findings: By laser microdissection cancer cell populations were harvested and subjected to whole genome expression analyses. Overall 473 and 541 genes were significantly regulated, when cancer versus transgenic and non-transgenic cells were compared, giving rise to three distinct and one common regulatory gene network. At advanced stages of tumor growth predominately repression of gene expression was observed, but genes previously shown to be upregulated in dysplasia were also up-regulated in solid tumors. Regulation of developmental programs as well as epithelial mesenchymal and mesenchymal endothelial transition was a hall mark of adenocarcinomas. Additionaly, genes coding for cell adhesion, i.e. the integrins and the tight and gap junction proteins were repressed, whereas ligands for receptor tyrosine kinase such as epi- and amphiregulin were up-regulated. Notably, Vegfr- 2 and its ligand Vegfd, as well as Notch and Wnt signalling cascades were regulated as were glycosylases that influence cellular recognition. Other regulated signalling molecules included guanine exchange factors that play a role in an activation of the MAP kinases while several tumor suppressors i.e. Mcc, Hey1, Fat3, Armcx1 and Reck were significantly repressed. Finally, probable molecular switches forcing dysplastic cells into malignantly transformed cells could be identified. Conclusions/Significance: This study provides insight into molecular pertubations allowing dysplasia to progress further to adenocarcinoma induced by exaggerted c-Raf kinase activity

The effect of victim age on police authorisation of charges in cases of child sexual abuse

In the study, a cohort of 440 child sexual abuse cases were used to model the effect of victim age on police authorisation of charges. Linear and quadratic effects of age were modelled in a logistic regression that controlled for case characteristics and evidence. The quadratic effect of victim age was strengthened when control variables were included in the model and the linear effect of age was not significant in the final model. The results indicated that cases involving victims in middle childhood had a higher proportion of suspects charged than cases involving victims in early childhood and adolescence. Possible mediators of the relationship between victim age and charges were explored and it was found that cases with older victims had a higher prevalence of extra-familial abuse and suspect confessions, and these factors had a positive effect on the proportion of suspects charged. Possible explanations for the quadratic effect of victim age and mediation are discussed