Novel methods based on regression techniques to analyze multistate models and high-dimensional omics data.

The dissertation is based on four distinct research projects that are loosely interconnected by the common link of a regression framework. Chapter 1 provides an introductory outline of the problems addressed in the projects along with a detailed review of the previous works that have been done on them and a brief discussion on our newly developed methodologies. Chapter 2 describes the first project that is concerned with the identification of hidden subject-specific sources of heterogeneity in gene expression profiling analyses and adjusting for them by a technique based on Partial Least Squares (PLS) regression, in order to ensure a more accurate inference on the expression pattern of the genes over two different varieties of samples. Chapter 3 focuses on the development of an R package based on Project 1 and its performance evaluation with respect to other popular software dealing with differential gene expression analyses. Chapter 4 covers the third project that proposes a non-parametric regression method for the estimation of stage occupation probabilities at different time points in a right-censored multistate model data, using an Inverse Probability of Censoring (IPCW) (Datta and Satten, 2001) based version of the backfitting principle (Hastie and Tibshirani, 1992). Chapter 5 describes the fourth project which deals with the testing for the equality of the residual distributions after adjusting for available covariate information from the right censored waiting times of two groups of subjects, by using an Inverse Probability of Censoring weighted (IPCW) version of the Mann-Whitney U test

The Impact of Caffeine and Coffee on Human Health

The purpose of this Special Issue is to provide a thorough and up-to-date presentation of research investigating the impact of coffee and/or caffeine intake on various health outcomes. Areas of interest include, but are not limited to, the following topics: Human clinical trials of coffee or caffeine use in relation to disease or intermediate phenotypes. Epidemiological studies of habitual coffee or caffeine intake in relation to human health, among the general public, as well as, among special populations (i.e., children, pregnant women, diabetics, cancer patients, hypertensives, etc.). Mechanisms of action of nutrients and other bioactive components of coffee/caffeine. Studies integrating genetic or physiological markers of coffee/caffeine intake to investigations of coffee and health

Compensating for unknown confounders in microarray data analysis using filtered permutations

Permutation of class labels is a common approach in microarray analysis. It is assumed to produce random score distributions, which are not affected by biological differences between samples. However, hidden confounding variables like the genetic background of patients or undetected experimental artifacts leave traces in the expression data contaminating the score distributions obtained from random permutations. While the effects of known confounders can be compensated using established methodology, little is known on how to deal with unknown confounders. We discuss a computational method called permutation filtering, which aims to borrow information across genes to detect and compensate the effects of unknown confounders

Effects of sodium benzoate on the innate immune response to gram-negative bacteria and Toll-like receptor stimulation

Sodium benzoate (NaB) is a sodium salt that is widely used in the pharmaceutical, cosmetic and food industries. This widespread use results in almost everybody in the world being exposed daily to this compound. Currently very little is known about the effects of NaB can have on the immune response, even though it has been associated with the clinical course of chronic inflammatory diseases, such as orofacial granulomatosis and neurodegenerative disorders. Here, I show that THP-1 cells, a monocytic human cell line presents an altered immune response when exposed to NaB. Immunologically stimulated THP-1 cells in the presence of NaB secreted reduced levels of IL6 and IL1β and higher levels of TNF, while other cytokines such as IP10 and IL8 were unaffected. The inhibitory effect in IL6 and IL1β secretion was a consequence of a free radical scavenging characteristic of NaB, which neutralizes the reactive oxygen species (ROS) generated downstream of TLR activation. This resulted in the impairment of a secondary signalling event, which is required to fully activate the cells immune response. The use of microarray analysis in combination with q quantitative proteomic analysis revealed that NaB has a significant effect on the THP-1 cells beyond the alteration in cytokine secretion. NaB also interferes with cellular amino acid metabolism and has a major attenuating effect on the immune response. Taken together, these results suggest that NaB is not inert and has a major effect on a cells ability to mount an immune response. These findings could have major implications in how NaB is used in the future and in particular if it can be beneficial as a treatment for chronic inflammatory diseases, such as diabetes, atherosclerosis, rheumatoid arthritis, neurodegenerative disorders, and so on. On the other hand, by disturbing the inflammatory response, NaB could have a negative impact on other conditions such as orofacial granulomatosis. Further work will be needed to determine the role NaB plays in human inflammatory diseases

Urological Cancer 2021

Cancer of the urological sphere is a disease continuously increasing in numbers in the statistics of tumor malignancies in Western countries. Although this fact is mainly due to the contemporary increase of life expectancy of the people in these geographic areas, many other factors do contribute as well to this growth. Urological cancer is a complex and varied disease of different organs and mainly affects the male population. In fact, kidney, prostate, and bladder cancer are regularly included in the top-ten list of the most frequent neoplasms in males in most statistics. The female population, however, has also increasingly found itself affected by renal and bladder cancer in the last decade. Considering these altogether, urological cancer is a problem of major concern in developed societies. This Topic Issue of Cancers intends to shed some light into the complexity of this field and will consider all useful and appropriate contributions that scientists and clinicians may provide to improve urological cancer knowledge for patients’ benefit. The precise identification of the molecular routes involved, the diagnostic pathological criteria in the grey zones, the dilemma of T1G3 management, and the possible treatment options between superficial, nonmuscle-invasive and muscle-invasive diseases will be particularly welcomed in this Issue