Pravastatin inhibits cell proliferation and increased MAT1A expression in hepatocarcinoma cells and in vivo models

Background: Statins may have therapeutic effects on hepatocarcinoma (HCC). This type of disorder is the most common malignant primary tumour in the liver. Our objective was to determine whether pravastatin had a therapeutic effect in vitro and in vivo models. Method: We design in vitro and in vivo model. In vitro we used PLC and determine cell proliferation. In vivo, we used and animal model to determined, PCNA and MAT1A expression and transaminases levels. Results: We found that pravastatin decreases cell proliferation in vitro (cell proliferation in pravastatin group was 82%, in sorafenib group 51% and in combined group 40%) and in vivo (in pravastatin group 80%, in sorafenib group 76.4% and in combined group 72.72%). The MAT1A levels, was significantly higher in Pravastatin group (D 62%, P 94%, S 71%, P + S 91%). The transaminases levels, decreased significantly in Pravastatin group (GOT and GPT levels D 619.5 U/L; 271 U/L) (P 117.5 U/L; 43.5 U/L) (S 147 U/L; 59 U/L) (P + S 142 U/L; 59 U/L). Conclusion: The combination of pravastatin + sorafenib were more effective than Sorafenib alone.

Sampling and learning the Mallows and Generalized Mallows models under the Cayley distance

[EN]The Mallows and Generalized Mallows models are compact yet powerful and natural ways of representing a probability distribution over the space of permutations. In this paper we deal with the problems of sampling and learning (estimating) such distributions when the metric on permutations is the Cayley distance. We propose new methods for both operations, whose performance is shown through several experiments. We also introduce novel procedures to count and randomly generate permutations at a given Cayley distance both with and without certain structural restrictions. An application in the field of biology is given to motivate the interest of this model.

Sampling and learning the Mallows and Weighted Mallows models under the Hamming distance

[EN]In this paper we deal with distributions over permutation spaces. The Mallows model is the mode l in use. The associated distance for permutations is the Hamming distance.

An R package for permutations, Mallows and Generalized Mallows models

[EN]Probability models on permutations associate a probability value to each of the permutations on n items. This paper considers two popular probability models, the Mallows model and the Generalized Mallows model. We describe methods for making inference, sampling and learning such distributions, some of which are novel in the literature. This paper also describes operations for permutations, with special attention in those related with the Kendall and Cayley distances and the random generation of permutations. These operations are of key importance for the efficient computation of the operations on distributions. These algorithms are implemented in the associated R package. Moreover, the internal code is written in C++.

An investigation of imputation methods for discrete databases and multi-variate time series

When it comes to information sets in real life, often pieces of the whole set may not be available. This problem can find its origin in various reasons, describing therefore different patterns. In the literature, this problem is known as Missing Data. This issue can be fixed in various ways, from not taking into consideration incomplete observations, to guessing what those values originally were, or just ignoring the fact that some values are missing. The methods used to estimate missing data are called Imputation Methods. The work presented in this thesis has two main goals. The first one is to determine whether any kind of interactions exists between Missing Data, Imputation Methods and Supervised Classification algorithms, when they are applied together. For this first problem we consider a scenario in which the databases used are discrete, understanding discrete as that it is assumed that there is no relation between observations. These datasets underwent processes involving different combina- tions of the three components mentioned. The outcome showed that the missing data pattern strongly influences the outcome produced by a classifier. Also, in some of the cases, the complex imputation techniques investigated in the thesis were able to obtain better results than simple ones. The second goal of this work is to propose a new imputation strategy, but this time we constrain the specifications of the previous problem to a special kind of datasets, the multivariate Time Series. We designed new imputation techniques for this particular domain, and combined them with some of the contrasted strategies tested in the pre- vious chapter of this thesis. The time series also were subjected to processes involving missing data and imputation to finally propose an overall better imputation method. In the final chapter of this work, a real-world example is presented, describing a wa- ter quality prediction problem. The databases that characterized this problem had their own original latent values, which provides a real-world benchmark to test the algorithms developed in this thesis.

Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity

Background: Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is still considered an unmet medical need. Methodology and Principal Findings: The interaction between Apaf-1 and the inhibitors was confirmed by NMR. Target specificity was evaluated in cellular models by siRNa based approaches. Cell recovery was confirmed by MTT, clonogenicity and flow cytometry assays. The efficiency of the compounds as antiapoptotic agents was tested in cellular and in vivo models of protection upon cisplatin induced ototoxicity in a zebrafish model and from hypoxia and reperfusion kidney damage in a rat model of hot ischemia. Conclusions: Apaf-1 inhibitors decreased Cytc release and apoptosome-mediated activation of procaspase-9 preventing cell and tissue damage in ex vivo experiments and in vivo animal models of apoptotic damage. Our results provide evidence that Apaf-1 pharmacological inhibition has therapeutic potential for the treatment of apoptosis-related diseases.