Ridge estimation of the VAR(1) model and its time series chain graph from multivariate time‐course omics data

Omics experiments endowed with a time‐course design may enable us to uncover the dynamic interplay among genes of cellular processes. Multivariate techniques (like VAR(1) models describing the temporal and contemporaneous relations among variates) that may facilitate this goal are hampered by the high‐dimensionality of the resulting data. This is resolved by the presented ridge regularized maximum likelihood estimation procedure for the VAR(1) model. Information on the absence of temporal and contemporaneous relations may be incorporated in this procedure. Its computational efficient implemention is discussed. The estimation procedure is accompanied with an LOOCV scheme to determine the associated penalty parameters. Downstream exploitation of the estimated VAR(1) model is outlined: an empirical Bayes procedure to identify the interesting temporal and contemporaneous relationships, impulse response analysis, mutual information analysis, and covariance decomposition into the (graphical) relations among variates. In a simulation study the presented ridge estimation procedure outperformed a sparse competitor in terms of Frobenius loss of the estimates, while their selection properties are on par. The proposed machinery is illustrated in the reconstruction of the p53 signaling pathway during HPV‐induced cellular transformation. The methodology is implemented in the ragt2ridges R‐package available from CRAN.     

Determination of plasma trace elements in tumor-bearing animals by proton-induced X-ray emission spectroscopy

Although altered levels of circulating essential trace elements are known to accompany malignant disease, the lack of sensitivity of conventional detection methods has generally limited their study to clinical conditions involving extensive disease (i.e., significant tumor burden). As such, the application of altered trace element levels as potential prognostic guides or as response indicators subsequent to treatment has been of limited use. During this study, proton-induced X-ray emission spectroscopy was evaluated as a tool to determine trace element imbalances in a murine tumor model. Using plasma from C57B1/6 mice bearing the syngeneic Lewis lung carcinoma (LLCa), levels of Fe, Cu, and Zn, as well as changes in the Cu/Zn ratio, were measured in animals carrying an increasing primary tumor burden. The plasma levels of Fe, Cu, and Zn were found to decrease significantly 7 d following implants of LLCa cells with no significant change observed in the Cu/Zn ratio. By d 21, however, an increase in the Cu/Zn ratio was found to accompany increased growth of the LLCa tumor; the plasma levels of Cu had returned to normal levels, whereas both the Fe and Zn plasma levels remained lowered. Collectively, the results suggest that although a net change in individual plasma trace element concentrations might not be accurately associated with tumor growth, a clear relationship was established between the Cu/Zn ratio and tumor size.     

Quantitative analysis of intra-fractional variation in CT-based image guided brachytherapy for cervical cancer patients

We quantified intra-fractional dose variation and organ movement during CT-based 3D-image guided brachytherapy (3D-IGBT) in cervical cancer patients. Fifteen patients who underwent CT-based 3D-IGBT were studied. For all patients, pre-delivery CT for treatment planning after applicator insertion and post-delivery CT after dose delivery without changing the applicator position were acquired. Pre- and post-delivery CT were rigidly fused by matching the inserted applicator and planned dose on pre-delivery CT (pre-delivery dose) was mapped on post-delivery CT (post-delivery dose). D2, D1, and D0.1 cm³ of the rectum and bladder were compared between pre- and post-delivery doses with contours on each CT image. Organ movement and deformation was evaluated using deformation vector fields calculated by deformable image registration between pre- and post-delivery CT. We also evaluated dose variation and DVF between with and without a catheter to control filling. Differences in all DVH parameters were <±3% in physical dose and ± 5% in EQD2. However, a > 15% dose difference was found in 13.8% of the fractions in rectum D2 cm³ and in 11.1% of those in bladder D2 cm³. The mean value of DVF for bladder was larger than that of rectum, especially for the superior-inferior (S-I) direction. Insertion catheters in bladder reduced mean dose and DVF variation compared with that of without catheters. In fraction groups with large dose increasing, DVF in the S-I direction was significantly larger than that of other fraction groups. Our results indicated that preparation is needed to reduce changes in the S-I direction affect dose variation.