Citations

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.

Background —This study applied the New York State conventional coronary angioplasty (PTCA) model of clinical outcomes to evaluate whether it has relevance in the current era of stent implantation. The model was developed in 62 670 patients treated with conventional PTCA from 1991 to 1994 to risk adjust mortality and bypass surgery after PTCA. Since then, stents have become the dominant form of intervention. Whether that model remains relevant is uncertain. Methods and Results —All patients undergoing stenting at the Mayo Clinic from 1995 to 1998 were analyzed for in-hospital mortality, bypass surgery performed after attempted stenting, and longer-term mortality. No patients were excluded. The New York model was used to risk adjust and predict in-hospital and follow-up mortality. There were 3761 patients with 4063 procedural admissions for stenting; 6472 target vessel segments were attempted, and 96.1% of procedures were successful. With the New York multivariable risk factor equation, 79 in-hospital deaths were expected (1.95%); 66 deaths (1.62%) were observed. The New York model risk score in a logistic regression model was the most significant factor associated with in-hospital mortality (OR, 1.86; P <0.001). During a mean follow-up of 1.2±1.0 years, there were 154 deaths. Multivariable analysis documented 6 factors associated with subsequent mortality; New York risk score was the most significant (χ 2 =16.64, P =0.0001). Conclusions —Although the New York mortality model was developed in an era of conventional angioplasty, it remains relevant in patients undergoing stenting. The risk score derived from that model is the variable most significantly associated with not only in-hospital but also longer-term outcome.

From 1957 through 1971, 18 patients whose ages ranged from 10 months to 18 years underwent surgical correction of tetralogy of Fallot with absent pulmonary valve. All patients had associated pulmonary arterial aneurysms; in two the left pulmonary artery also was absent. Right middle lobectomy had been performed previously on one patient for lobar emphysema; seven other patients had recurrent pulmonary infections. The ventricular septal defect was closed with a patch in 12 patients and by direct suture in 6. Concomitant infundibular resection was done in all. In four the narrow pulmonary valve annulus was enlarged with an outflow patch, and multiple radial incisions were made in the valve annulus in seven others. The pulmonary arterial aneurysms were not resected in any patients. There were three hopsital deaths (17%) and two late deaths. Complete heart block developed intraoperatively in three patients, all operated on prior to 1963, contributing to the early death of one patient and to the late deaths of the other two. In a follow-up of all 13 survivors at 8 months to 15 years (median 6 years), results were excellent and equal to those of patients who have undergone repair of tetralogy of Fallot with pulmonary valve.

BACKGROUND: Optimal titration of inspired oxygen is important to prevent hyperoxia in mechanically ventilated patients in ICUs. There is mounting evidence of the deleterious effects of hyperoxia; however, there is a paucity of data about F IO 2 practice and oxygen exposure among patients in ICUs. We therefore sought to assess excessive F IO 2 exposure in mechanically ventilated patients with acute lung injury and to evaluate the effect on pulmonary outcomes. METHODS: From a database of ICU patients with acute lung injury identified by prospective electronic medical record screening, we identified those who underwent invasive mechanical ventilation for > 48 hours from January 1 to December 31, 2008. Ventilator settings, including F IO 2 and corresponding S pO 2 , were collected from the electronic medical record at 15-min intervals for the first 48 hours. Excessive F IO 2 was defined as F IO 2 > 0.5 despite S pO 2 > 92%. The association between the duration of excessive exposure and pulmonary outcomes was assessed by change in oxygenation index from baseline to 48 hours and was analyzed by univariate and multivariate linear regression analysis. RESULTS: Of 210 patients who met the inclusion criteria, 155 (74%) were exposed to excessive F IO 2 for a median duration of 17 hours (interquartile range 7.5–33 h). Prolonged exposure to excessive F IO 2 correlated with worse oxygenation index at 48 hours in a dose-response manner ( P < .001.). Both exposure to higher F IO 2 and longer duration of exposure were associated with worsening oxygenation index at 48 hours ( P < .001), more days on mechanical ventilation, longer ICU stay, and longer hospital stay ( P = .004). No mortality difference was noted. CONCLUSIONS: Excessive oxygen supplementation is common in mechanically ventilated patients with ALI and may be associated with worsening lung function.