CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial

Background Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms. Methods We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor-positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction-based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43). Conclusions CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxife

Review of the development of cesium iodide photocathodes for application to large RICH detectors

CsI photocathodes were studied in order to evaluate their potential use as large photo converters in RICH detectors for the PID system of ALICE at LHC in heavy-ion collider mode. It has been demonstrated that a quantum efficiency close to the reference value obtained on small samples can be obtained on CsI layers evaporated on large pad electrodes operated in a MWPC at atmospheric pressure. We present a survey of the results obtained in the laboratory on small samples irradiated with UV-monochromatic beams and with large area RICH detectors of proximity-focusing geometry in a 3 GeV/c pion beam

Clinical and experimental efficacy of gemtuzumab ozogamicin in core binding factor acute myeloid leukemia

Leukemia-initiating cells of core binding factor (CBF) acute myeloid leukemia (AML) likely derive from early committed hematopoietic precursors expressing CD33. As such, targeting CD33 could ameliorate the chance of cure of CBF AML patients. We compared 12 CBF AML patients treated with Fludarabine, Cytarabine, Idarubicin and Gemtuzumab Ozogamicin (FLAI-GO regimen) with 25 CBF AML patients treated with the same schedule, but without GO. With the limit of small numbers, we observed a consistent trend toward better overall survival, disease free survival and event free survival in the FLAI-GO group. We also demonstrated the ability of GO to induce the disappearance in vitro of the AML1-ETO molecular transcript in a polymerase chain reaction-positive graft without decreasing the clonogenic potential of CD34+/CD38- cells. This represent the proof of principle for using GO in a purging strategy before autologous stem cell transplantation. Therefore, our data argue in favor of the reinstitution of GO in the therapy of CBF AML

On reliable discovery of molecular signatures

<p>Abstract</p> <p>Background</p> <p>Molecular signatures are sets of genes, proteins, genetic variants or other variables that can be used as markers for a particular phenotype. Reliable signature discovery methods could yield valuable insight into cell biology and mechanisms of human disease. However, it is currently not clear how to control error rates such as the false discovery rate (FDR) in signature discovery. Moreover, signatures for cancer gene expression have been shown to be unstable, that is, difficult to replicate in independent studies, casting doubts on their reliability.</p> <p>Results</p> <p>We demonstrate that with modern prediction methods, signatures that yield accurate predictions may still have a high FDR. Further, we show that even signatures with low FDR may fail to replicate in independent studies due to limited statistical power. Thus, neither stability nor predictive accuracy are relevant when FDR control is the primary goal. We therefore develop a general statistical hypothesis testing framework that for the first time provides FDR control for signature discovery. Our method is demonstrated to be correct in simulation studies. When applied to five cancer data sets, the method was able to discover molecular signatures with 5% FDR in three cases, while two data sets yielded no significant findings.</p> <p>Conclusion</p> <p>Our approach enables reliable discovery of molecular signatures from genome-wide data with current sample sizes. The statistical framework developed herein is potentially applicable to a wide range of prediction problems in bioinformatics.</p

Low Emission Small Two-Stroke Engines

The scavenging process of two-stroke engines is unfavorably characterized by the loss of large part of the fresh charge from the exhaust port. Besides, bad combustion and misfire occur at light loads, because of the excessive ratio of residual gas to fresh gas within the cylinder. To avoid fuel loss from the exhaust port, the solution is direct fuel injection, as well as charge stratification is the solution for light-load operation. With direct fuel injection and charge stratification, the simple two-stroke engine with loop-and-crankcase scavenging for small motorbikes can satisfy present exhaust emission limits even without catalytic converter. Direct injection and charge stratification equalize two-stroke and four-stroke engines as regards exhaust emissions and fuel economy, or give a slight superiority to two-stroke engines thanks to their intrinsic EGR and low friction. Besides, two-stroke engines deliver higher torque, especially at low engine speeds and, of course, have double firing frequency that improves torque regularity. High-pressure liquid fuel injection is able to control the mixing process inside the cylinder for getting either stratified charge at partial loads or quasi-homogeneous conditions, as it is required at full load. The most difficult aims are keeping stable stratification when engine operating conditions change and, at very light loads, avoiding excessive dilution and spreading of fuel vapour in consequence of burned gas expansion. New-concept engine designs are shown in this paper. Shapes of piston and head, together with scavenging-duct orientation have been optimised to obtain stable in-cylinder flow field features (independently of engine speed) and proper fuel distribution at ignition time. Computational Fluid Dynamics (CFD) predictions at different loads and speeds are reported and discussed