MRNA expression profiles of colorectal liver metastases as a novel biomarker for early recurrence after partial hepatectomy

Background: Identification of specific risk groups for recurrence after surgery for isolated colorectal liver metastases (CRLM) remains challenging due to the heterogeneity of the disease. Classical clinicopathologic parameters have limited prognostic value. The aim of this study was to identify a gene expression signature measured in CRLM discriminating early from late recurrence after partial hepatectomy. Methods: CRLM from two patient groups were collected: I) with recurrent disease ≤12 months after surgery (N = 33), and II) without recurrences and disease free for ≥36 months (N = 30). The patients were clinically homogeneous; all had a low clinical risk score (0-2) and did not receive (neo-) adjuvant chemotherapy. Total RNA was hybridised to Illumina arrays, and processed for analysis. A leave-one-out cross validation (LOOCV) analysis was performed to identify a prognostic gene expression signature. Results: LOOCV yielded an 11-gene profile with prognostic value in relation to recurrent disease ≤12 months after partial hepatectomy. This signature had a sensitivity of 81.8%, with a specificity of 66.7% for predicting recurrences (≤12 months) versus no recurrences for at least 36 months after surgery (X2 P < 0.0001). Conclusion: The current study yielded an 11-gene signature at mRNA level in CRLM discriminating early from late or no relapse after partial hepatectomy

Possible shears bands in At204 and Fr206, and identification of excited states in Fr205,207

Neutron-deficient astatine and francium nuclei were produced in the reaction 30Si+181Ta→211Fr* at 152 MeV. The evaporation residues from this very fissile system were selected with the HERCULES-II detector system and residue-gated γ rays were measured with Gammasphere. Excited states were observed for the first time in Fr205,207, as well as sequences of low-energy transitions between high-spin states in At204 and Fr206. These latter structures have properties similar to those associated with magnetic rotation (shears bands) in lead nuclei. Comparisons with established shears bands are presented and prospects for the magnetic-rotation phenomenon near the predicted N=120 "magic" number are explored

Recent Advances in Understanding Particle Acceleration Processes in Solar Flares

We review basic theoretical concepts in particle acceleration, with particular emphasis on processes likely to occur in regions of magnetic reconnection. Several new developments are discussed, including detailed studies of reconnection in three-dimensional magnetic field configurations (e.g., current sheets, collapsing traps, separatrix regions) and stochastic acceleration in a turbulent environment. Fluid, test-particle, and particle-in-cell approaches are used and results compared. While these studies show considerable promise in accounting for the various observational manifestations of solar flares, they are limited by a number of factors, mostly relating to available computational power. Not the least of these issues is the need to explicitly incorporate the electrodynamic feedback of the accelerated particles themselves on the environment in which they are accelerated. A brief prognosis for future advancement is offered.Comment: This is a chapter in a monograph on the physics of solar flares, inspired by RHESSI observations. The individual articles are to appear in Space Science Reviews (2011

Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab’)2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients

Methods to adjust for confounding: propensity scores and instrumental variables

In the evaluation of the effect of different treatments well-conducted randomized controlled trials have been widely accepted as the scientific standard. When on the other hand observational studies are used to assess treatment effects, the absence of a randomized assignment of treatments will in general result in treatment groups that are systematically different on factors that can be alternative explanations for the observed treatment effect. Therefore, in these types of studies is adjustment for confounding necessary. An overview of such methods is given and two methods are further described, evaluated and applied in real data sets. Furthermore, improvements are suggested. One of these adjustment methods, propensity scores, is increasingly used in the medical literature as an alternative for traditional regression-based methods like logistic regression and Cox proportional hazards regression. Nonetheless, an important advantage of propensity scores is frequently overlooked by researchers, that is, its treatment effect estimate is in general closer to the true average treatment effect than regression methods using the odds ratio or the hazard ratio. The difference can be substantial, especially when the number of confounding factors is more than 5, the treatment effect is larger than an odds ratio of 1.25 (or smaller than 0.8) or the incidence proportion is between 0.05 and 0.95. An important step in the application of propensity score methods is the creation of the propensity score model, including the check for balance. In many applications this model is routinely chosen and information on the balance of covariates between treatment groups is missing. We proposed to use a measure for balance, the overlapping coefficient, to select the best propensity score model and to report the amount of balance uniformly. Its inverse association with bias and the low mean squared error support the use of this measure. For smaller sample sizes the method does not seem to work well for model selection purposes. We also explored alternative measures, the Kolmogorov-Smirnov distance and the Lévy metric, but these were slightly less promising. The other adjustment method that has been evaluated, is the method of instrumental variables. Its potential ability to adjust for all confounders, whether observed or not is an attractive property. We applied this method on censored survival data and used the difference in survival probabilities as the treatment effect. Formulas for standard errors are provided, which can be large in absolute value in case of a low number of events or at the end of the survival curve. Nonetheless, this method is worthwile when a suitable instrumental variable can be found or can be created. In the literature a warning can be found against a weak correlation between the instrumental variable and treatment. We demonstrated the existence of an upper bound on this correlation, which can be a practical limitation when considerable confounding exists. This can result in a fairly weak instrument in order to fulfill the main assumption of the method, or worse, can indicate a violation of the main assumption when the instrumental variable turns out to be strong