Alzheimer Disease Diagnosis based on Automatic Spontaneous Speech Analysis

Alzheimer’s disease (AD) is the most prevalent form of progressive degenerative dementia and it has a high socio-economic impact in Western countries, therefore is one of the most active research areas today. Its diagnosis is sometimes made by excluding other dementias, and definitive confirmation must be done trough a post-mortem study of the brain tissue of the patient. The purpose of this paper is to contribute to improvement of early diagnosis of AD and its degree of severity, from an automatic analysis performed by non-invasive intelligent methods. The methods selected in this case are Automatic Spontaneous Speech Analysis (ASSA) and Emotional Temperature (ET), that have the great advantage of being non invasive, low cost and without any side effects

On Automatic Diagnosis of Alzheimer's Disease based on Spontaneous Speech Analysis and Emotional Temperature

Alzheimer's disease is the most prevalent form of progressive degenerative dementia; it has a high socio-economic impact in Western countries. Therefore it is one of the most active research areas today. Alzheimer's is sometimes diagnosed by excluding other dementias, and definitive confirmation is only obtained through a post-mortem study of the brain tissue of the patient. The work presented here is part of a larger study that aims to identify novel technologies and biomarkers for early Alzheimer's disease detection, and it focuses on evaluating the suitability of a new approach for early diagnosis of Alzheimer’s disease by non-invasive methods. The purpose is to examine, in a pilot study, the potential of applying Machine Learning algorithms to speech features obtained from suspected Alzheimer sufferers in order help diagnose this disease and determine its degree of severity. Two human capabilities relevant in communication have been analyzed for feature selection: Spontaneous Speech and Emotional Response. The experimental results obtained were very satisfactory and promising for the early diagnosis and classification of Alzheimer’s disease patients

On the Analysis of Speech and Disfluencies for Automatic Detection of Mild Cognitive Impairment

Alzheimer's disease is characterized by a progressive and irreversible cognitive deterioration. In a previous stage, the so-called Mild Cognitive Impairment or cognitive loss appears. Nevertheless, this previous stage does not seem sufficiently severe to interfere in independent abilities of daily life, so it is usually diagnosed inappropriately. Thus, its detection is a crucial challenge to be addressed by medical specialists. This paper presents a novel proposal for such early diagnosis based on automatic analysis of speech and disfluencies, and Deep Learning methodologies. The proposed tools could be useful for supporting Mild Cognitive Impairment diagnosis. The Deep Learning approach includes Convolutional Neural Networks and nonlinear multifeature modeling. Additionally, an automatic hybrid methodology is used in order to select the most relevant features by means of nonparametric Mann-Whitney U test and Support Vector Machine Attribute evaluation.This work has been supported by FEDER and MICINN, TEC2016-77,791-C4-2-R, and UPV/EHU-Basque Research Groups IT11156 and Basque Country EleKin Research Grou

ZMC 211-3 - KAEDAH MATEMATIK II MAC-APRIL 1989.pdf

The work presented here is part of a larger study to identify novel technologies and biomarkers for early Alzheimer disease (AD) detection and it focuses on evaluating the suitability of a new approach for early AD diagnosis by non-invasive methods. The purpose is to examine in a pilot study the potential of applying intelligent algorithms to speech features obtained from suspected patients in order to contribute to the improvement of diagnosis of AD and its degree of severity. In this sense, Artificial Neural Networks (ANN) have been used for the automatic classification of the two classes (AD and control subjects). Two human issues have been analyzed for feature selection: Spontaneous Speech and Emotional Response. Not only linear features but also non-linear ones, such as Fractal Dimension, have been explored. The approach is non invasive, low cost and without any side effects. Obtained experimental results were very satisfactory and promising for early diagnosis and classification of AD patients

Feature selection for spontaneous speech analysis to aid in Alzheimer’s disease diagnosis: A fractal dimension approach

Alzheimer’s disease (AD) is the most prevalent form of degenerative dementia; it has a high socio-economic impact in Westerncountries. The purpose of our project is to contribute to earlier diagnosis of AD and allow better estimates of its severity by usingautomatic analysis performed through new biomarkers extracted through non-invasive intelligent methods. The method selectedis based on speech biomarkers derived from the analysis of spontaneous speech (SS). Thus the main goal of the present work isfeature search in SS, aiming at pre-clinical evaluation whose results can be used to select appropriate tests for AD diagnosis. Thefeature set employed in our earlier work offered some hopeful conclusions but failed to capture the nonlinear dynamics of speechthat are present in the speech waveforms. The extra information provided by the nonlinear features could be especially useful whentraining data is limited. In this work, the fractal dimension (FD) of the observed time series is combined with linear parameters inthe feature vector in order to enhance the performance of the original system while controlling the computational cost.© 2014 Elsevier Ltd. All rights reserved

Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition

Selenium supplement has been shown in clinical trials to reduce the risk of different cancers including lung carcinoma. Previous studies reported that the antiproliferative and pro-apoptotic activities of methylseleninic acid (MSA) in cancer cells could be mediated by inhibition of the PI3K pathway. A better understanding of the downstream cellular targets of MSA will provide information on its mechanism of action and will help to optimize its use in combination therapies with PI3K inhibitors. For this study, the effects of MSA on viability, cell cycle, metabolism, apoptosis, protein and mRNA expression, and reactive oxygen species production were analysed in A549 cells. FOXO3a subcellular localization was examined in A549 cells and in stably transfected human osteosarcoma U2foxRELOC cells. Our results demonstrate that MSA induces FOXO3a nuclear translocation in A549 cells and in U2OS cells that stably express GFP-FOXO3a. Interestingly, sodium selenite, another selenium compound, did not induce any significant effects on FOXO3a translocation despite inducing apoptosis. Single strand break of DNA, disruption of tumour cell metabolic adaptations, decrease in ROS production, and cell cycle arrest in G1 accompanied by induction of apoptosis are late events occurring after 24h of MSA treatment in A549 cells. Our findings suggest that FOXO3a is a relevant mediator of the antiproliferative effects of MSA. This new evidence on the mechanistic action of MSA can open new avenues in exploiting its antitumour properties and in the optimal design of novel combination therapies. We present MSA as a promising chemotherapeutic agent with synergistic antiproliferative effects with cisplatin. (C) 2015 Elsevier Ltd. All rights reserved.Ministerio de Ciencia e Innovacion, Spain [SAF2011-25726]; Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR)-Generalitat de Catalunya [2014SGR1017]; Ministerio de Economia y Competitividad, Spain [SAF2014-56059-R]; Fundacao para a Ciencia e a Tecnologia (FCT) Research Center [UID/BIM/04773/2013CBMR 1334]; National Institute of Health, USA [1R01CA118434-01A2, 1P01CA163223-01A1]; National Science Foundation, USA [EPS-0447479]; FCT [SFRH/BPD/84634/2012]; prize ICREA Academia for excellence in research; ICREA Foundation-Generalitat de Cataluny

Caracterització metabòlica de la transformació i la progressió tumoral i anàlisi de l'efecte de nous compostos amb potencial terapèutic

[cat] Aquesta Tesi doctoral aprofundeix en el coneixement del metabolisme cel·lular, concretament en el metabolisme central del carboni de cèl·lules no tumorals transfectades amb un oncogen (HRas) amb una mutació puntual (G12V), de cèl·lules no tumorals amb delecions puntuals en els enzims clau que controlen la progressió a través del cicle cel·lular (CDK4 i CDK6) o de cèl·lules tumorals tractades amb agents antitumorals. El metabolisme, vist com un nivell integrador de moltes de les vies de transducció de senyals, pot servir no només per entendre com es produeixen les alteracions que porten a l'adquisició d'un fenotip tumoral maligne, sinó que pot oferir una sèrie de dianes terapèutiques basades en impedir l'adaptació específica de la cèl·lula tumoral als canvis durant el procés de malignitat o davant tractaments antitumorals. Amb aquesta finalitat, en aquesta Tesi Doctoral se li ha donat especial importància a la síntesi i desenvolupament de nous compostos amb potencial antitumoral dels que s'ha fet un estudi molecular i metabòlic detallat per poder observar la resposta de la cèl·lula tumoral front de les pertorbacions provocades. El coneixement detallat dels efectes a nivell molecular i metabòlic de potencials fàrmacs és d'esperar que sigui de gran utilitat a l'hora de dissenyar teràpies combinades per potenciar sinergies entre fàrmacs i evitar els possibles efectes secundaris no desitjats. S'han utilitzat models in vitro i s'han estudiat les seves alteracions moleculars i metabòliques: en el primer capítol s'ha posat de manifest, mitjançant l'ús de fibroblasts embriogènics de ratolí deficients en CDK4, CDK6 i CDK2, que la inhibició de la transició G1 / S del cicle cel·lular reverteix l'ús de les branques oxidativa i no oxidativa de la ruta de les pentoses fosfat característica de tumors. A continuació, s'han caracteritzat nous inhibidors de CDK4 i CDK6 identificats amb eines bioinformàtiques en diferents línies cel·lulars per així millorar el disseny racional de noves teràpies dirigides a tumors deficients en el supressor tumoral p16INK4a i que mantinguin el pRB inalterat. En el tercer capítol es caracteritza una nova família de lactones sintètiques disubstituidas per validar els seus efectes antitumorals i inhibitoris de les proteïnes clau de la fase G1 del cicle cel·lular, CDK4 i CDK6. Els efectes moleculars o activitat dels compostos i la relació amb la seva estructura proporcionen informació valuosa per al disseny racional de noves teràpies. En el quart capítol s'analitzen els efectes moleculars de l'àcid metilselenínic. El compost és capaç de translocar FOXO al nucli i en cèl·lules de carcinoma humà de pulmó A-549 indueix efectes moleculars que són explicats pel nou mecanisme d'acció descrit. Finalment, en el capítol 5 s'aprofundeix sobre el perfil metabòlic associat a la transfecció de l'oncogen HRas amb una mutació puntual en el codó 12.[eng] There are numerous experimental evidences showing that a large number of tumours are associated with deregulation of cyclin D-CDK4/6-INK4a-pRb pathway, and in particular the reduction of normal levels of p16INK4a, a natural inhibitor of CDK4/6 protein. Therefore, obtaining inhibitors of these proteins can be extremely useful in selective therapeutic treatments against cancer. Currently there are molecules, some of them already in clinical phase, which inhibit CDK4/CDK6 competing with ATP. However, given the large number of kinase proteins that exist in the body, these molecules could cause numerous side effects. It is therefore of great interest to design specific inhibitors CDK4/CDK6 using a different strategy and eliminate these side effects. It is therefore expected that CDK4/CDK6 inhibitors developed in this work will have high practical applicability and usefulness in cancer treatment. The designed inhibitors mimic the binding site of p16 and not the binding ATP as most CDK inhibitors currently available and in consequence they will be highly specific to CDK4/6 kinases. Moreover, in this thesis we elucidated the mechanism of action of metilselenínic acid (MSeA). The treatment of MSeA on human lung carcinoma cell line A-549 provokes a cell cycle arrest in G1 phase of the cell cycle, apoptosis, reactive oxygen species detoxification at 24, 48 and 72h as well as metabolic effects at 24h that could be explained by the FOXO translocation to the nucleus. Furthermore, phenotypic specificity shown by different KRas transfectants raises the question whether metabolic adaptation of this mutated gene causes is specific from the mutated isoform, and thus is maintained by introducing mutated isoform of H-ras in mouse fibroblast cells. Thus, in this section of the work, we considered doing a metabolomic characterization of NIH-3T3 cells transfected with copies of HRas oncogene containing a substitution similar to those already tested in K-ras: replacement of glycine at position 12 by a valine. This would open the possibility of using a sensitivity analysis similar to that in KRas, which allows the specific design of therapies depending on the metabolic profile observed

Prediction of the skin permeability of topical drugs using in silico and in vitro models

The main challenge of topically applied drugs is to overcome the skin barrier to reach the site of action at the concentration needed for efficacy. In the research of new topical drugs, design of molecules with optimized properties for skin penetration is a key factor and assays for its characterization are needed. A group of 20 representative topical molecules of clinical use were studied in two in silico models (Potts & Guy and Barratt), and an in vitro assay with artificial membrane (Skin-PAMPA). A subset of 9 drugs were also evaluated in the Franz cells assay, formulated in a solvent and in a marketed formulation. Each assay allowed us to grade compounds according to their permeability value. Globally good alignments were found for the studied compounds when comparing models, although discrepancies for some compounds such as tazarotene, tacrolimus, ketoconazole and metronidazole were observed. Overall, the studied in silico and the in vitro models are useful tools to support selection and characterization of research compounds in terms of skin permeability. © 2019 Elsevier B.V.The authors would like to acknowledge Y. Carranza, L. Estrella, M. de Luca and J. Navarro for their excellent technical assistance, and M.I. Crespo and J. González for comments that greatly improved the manuscript. This work was supported by the Ministerio de Economía y Competitividad of the Spanish Government in the call for the “Retos-Colaboración 2014” [Project RTC-2014-1901-1 “Plataforma Tecnológica Innoderm”].Peer reviewe

Methylseleninic acid promotes Antitumour effects via nuclear FOXO3a translocation through Akt inhibition

Selenium supplement has been shown in clinical trials to reduce the risk of different cancers including lung carcinoma. Previous studies reported that the antiproliferative and pro-apoptotic activities of methylseleninic acid (MSA) in cancer cells could be mediated by inhibition of the PI3K pathway. A better understanding of the downstream cellular targets of MSA will provide information on its mechanism of action and will help to optimize its use in combination therapies with PI3K inhibitors. For this study, the effects of MSA on viability, cell cycle, metabolism, apoptosis, protein and mRNA expression, and reactive oxygen species production were analysed in A549 cells. FOXO3a subcellular localization was examined in A549 cells and in stably transfected human osteosarcoma U2foxRELOC cells. Our results demonstrate that MSA induces FOXO3a nuclear translocation in A549 cells and in U2OS cells that stably express GFP-FOXO3a. Interestingly, sodium selenite, another selenium compound, did not induce any significant effects on FOXO3a translocation despite inducing apoptosis. Single strand break of DNA, disruption of tumour cell metabolic adaptations, decrease in ROS production, and cell cycle arrest in G1 accompanied by induction of apoptosis are late events occurring after 24 h of MSA treatment in A549 cells. Our findings suggest that FOXO3a is a relevant mediator of the antiproliferative effects of MSA. This new evidence on the mechanistic action of MSA can open new avenues in exploiting its antitumour properties and in the optimal design of novel combination therapies. We present MSA as a promising chemotherapeutic agent with synergistic antiproliferative effects with cisplatin

Effect of propylene glycol on the skin penetration of drugs

Propylene glycol (PG) has been used in formulations as a co-solvent and/or to enhance drug permeation through the skin from topical preparations. Two skin in vitro permeation approaches are used to determine the effect of PG on drug penetration. The in vitro Skin-PAMPA was performed using 24 actives applied in aqueous buffer or PG. PG modulates permeability by increasing or diminishing it in the compounds with poor or high permeability, respectively. Percutaneous absorption using pigskin on Franz diffusion cells was performed on seven actives and their commercial formulations. The commercial formulations evaluated tend to have a lower permeability than their corresponding PG solutions but maintain the compound distribution in the different strata: stratum corneum, epidermis and dermis. The results indicate the enhancer properties of PG for all compounds, especially for the hydrophilic ones. Additionally, the Synchrotron-Based Fourier Transform Infrared microspectroscopy technique is applied to study the penetration of PG and the molecular changes that the vehicle may promote in the different skin layers. Results showed an increase of the areas under the curve indicating the higher amount of lipids in the deeper layers and altering the lipidic order of the bilayer structure to a more disordered lipid structure