Ibrahim-zada, Irada

Abstract Background Patient benefits from natural orifice transluminal endoscopic surgery (NOTES) are of interest in acute-care surgery. This review provides an overview of the historical development of NOTES procedures, and addresses their current uses and limitations for intra-abdominal emergency conditions. Methods A PubMed search was carried out for articles describing NOTES approaches for appendicectomy, percutaneous gastrostomy, hollow viscus perforation and pancreatic necrosectomy. Pertinent articles were reviewed and data on available outcomes synthesized. Results Emergency conditions in surgery tax the patient's cardiovascular and respiratory systems, and fluid and electrolyte balance. The operative intervention itself leads to an inflammatory response and blood loss, thus adding to the physiological stress. NOTES provides a minimally invasive alternative access to the peritoneal cavity, avoiding abdominal wall incisions. A clear advantage to the patient is evident with the implementation of an endoscopic approach to deal with inadvertently displaced percutaneous endoscopic gastrostomy tubes and perforated gastroduodenal ulcer. The NOTES approach appears less invasive for patients with infected pancreatic necrosis, in whom it allows surgical debridement and avoidance of open necrosectomy. Transvaginal appendicectomy is the second most frequently performed NOTES procedure after cholecystectomy. The NOTES concept has provided a change in perspective for intramural and transmural endoscopic approaches to iatrogenic perforations during endoscopy. Conclusion NOTES approaches have been implemented in clinical practice over the past decade. Selected techniques offer reduced invasiveness for patients with intra-abdominal emergencies, and may improve outcomes. Steady future development and adoption of NOTES are likely to follow as technology improves and surgeons become comfortable with the approaches.

Abstract Introduction: Androstenedione is a precursor for estrogen biosynthesis catalyzed by aromatase. Plasma androstenedione concentrations in postmenopausal women with early stage breast cancer display large interindividual variation (Ingle et al., Cancer Res. 70:3278–86, 2010). We performed a GWAS to identify single nucleotide polymorphisms (SNPs) associated with plasma levels of androstenedione in 776 postmenopausal women with resected early stage breast cancer. Methods: Plasma androstenedione concentrations were measured by GC-MS/MS. GWAS was performed using Illumina Human610-Quad BeadChips. The GWAS results were controlled for population stratification (PS) by Eigenstrat analyses. Plasma androstenedione concentrations were associated with genotype by using a quasi-likelihood model with adjustment for PS, BMI, age and other clinical variables associated with androstenedione concentrations (p<0.01). Imputation using HapMap2 data was performed within 200 kb on either side of regions containing SNPs with p<E-05. Results: 563,945 SNPs were analyzed, followed by imputation. The genotyped SNP with the lowest p value, rs4736317 (p=4.61E-06), was on chromosome 8 near the CYP11B1 and CYP11B2 genes. This SNP had a multiplicative effect of 1.128 (95% Cl: 1.07, 1.19) and a MAF of 0.40. After imputation, 20 SNPs with apparent p<E-06 were observed in this same region, with the lowest p value for rs9773022 (p=8.1E-08). We then performed functional genomic studies, and observed that two of the SNPs with low p values (rs4736312, p=1.49E-05 and rs4736350, p=6.34E-06) created apparent Oct-1 transcription factor binding sites (TFBS). Differential nuclear protein binding of Oct-1 to probes for these SNPs was verified with EMS and supershift assays using nuclear extract from A549 and NCI-H295R cells. Treatment of these two cell lines with 10 nM androstenedione led to the disruption of Oct-1 binding with the A (wild type) allele on rs4736312. rs4736312 is located in the 3'-UTR of CYP11B1 15 bp distant from response elements for the progesterone receptor and the glucocorticoid receptor. We also demonstrated that CYP11B1 and CYP11B2 were induced by estradiol in U2OS cell lines that express ER receptor and by androstenedione in H295R cells that express the androgen receptor. Transfection of a reporter gene construct with the rs4736312 SNP sequences into COS-1 and H295R cells suppressed reporter gene activity for the variant SNP sequence as compared to wild type, an observation that may correlate with the higher plasma levels of androstenedione in women (549× 328 vs 410×208 mean×SD, M/ml) with the variant allele. Conclusion: We have identified a series of SNPs in a region of chromosome 8 in and around CYP11B1 and CYP11B2 that are associated with elevated plasma androstenedione concentrations in postmenopausal women with resected early stage breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C114.