Novel gene signatures for stage classification of the squamous cell carcinoma of the lung.

The squamous cell carcinoma of the lung (SCLC) is one of the most common types of lung cancer. As GLOBOCAN reported in 2018, lung cancer was the first cause of death and new cases by cancer worldwide. Typically, diagnosis is made in the later stages of the disease with few treatment options available. The goal of this work was to find some key components underlying each stage of the disease, to help in the classification of tumor samples, and to increase the available options for experimental assays and molecular targets that could be used in treatment development. We employed two approaches. The first was based in the classic method of differential gene expression analysis, network analysis, and a novel concept known as network gatekeepers. The second approach was using machine learning algorithms. From our combined approach, we identified two sets of genes that could function as a signature to identify each stage of the cancer pathology. We also arrived at a network of 55 nodes, which according to their biological functions, they can be regarded as drivers in this cancer. Although biological experiments are necessary for their validation, we proposed that all these genes could be used for cancer development treatments.

Anticipation of ventricular tachyarrhythmias by a novel mathematical method: Further insights towards an early warning system in implantable cardioverter defibrillators.

Implantable cardioverter defibrillators (ICD) are the most effective therapy to terminate malignant ventricular arrhythmias (VA) and therefore to prevent sudden cardiac death. Until today, there is no way to predict the onset of such VA. Our aim was to develop a mathematical model that could predict VA in a timely fashion. We analyzed the time series of R-R intervals from 3 groups. Two groups from the Spontaneous Ventricular Tachyarrhythmia Database (v 1.0) were analyzed from a set of 81 pairs of R-R interval time series records from patients, each pair containing one record before the VT episode (Dataset 1A) and one control record which was obtained during the follow up visit (Dataset 1B). A third data set was composed of the R-R interval time series of 54 subjects without a significant arrhythmia heart disease (Dataset 2). We developed a new method to transform a time series into a network for its analysis, the ε-regular graphs. This novel approach transforms a time series into a network which is sensitive to the quantitative properties of the time series, it has a single parameter (ε) to be adjusted, and it can trace long-range correlations. This procedure allows to use graph theory to extract the dynamics of any time series. The average of the difference between the VT and the control record graph degree of each patient, at each time window, reached a global minimum value of -2.12 followed by a drastic increase of the average graph until reaching a local maximum of 5.59. The global minimum and the following local maxima occur at the windows 276 and 393, respectively. This change in the connectivity of the graphs distinguishes two distinct dynamics occurring during the VA, while the states in between the 276 and 393, determine a transitional state. We propose this change in the dynamic of the R-R intervals as a measurable and detectable "early warning" of the VT event, occurring an average of 514.625 seconds (8:30 minutes) before the onset of the VT episode. It is feasible to detect retrospectively early warnings of the VA episode using their corresponding ε-regular graphs, with an average of 8:30 minutes before the ICD terminates the VA event.

How to eliminate taeniasis/cysticercosis: porcine vaccination and human chemotherapy (Part 2).

BACKGROUND: The application of effective vaccines against pig cysticercosis and mass chemotherapy against pig cysticercosis and human taeniasis have shown the feasibility of interrupting the parasite's life cycle in endemic areas. METHODS: A mathematical model that divides the population into susceptible, infected, and vaccinated individuals is formulated. The model is based upon the life cycle of the parasite. Computer numerical simulation experiments to evaluate the impact of pig vaccination under different vaccination schedules, and combined intervention strategies including pig vaccination and anthelmintic treatment against human taeniasis are carried out. RESULTS: Vaccination against either pig cysticercosis or against human taeniasis will influence the transmission dynamics not only among vaccinees but also the dynamics of the other hosts as well. When the protective efficacy and/or the coverage rate is less than 100%, different mass interventions like vaccinating the pig population twice in combination with chemotherapeutic treatment against human taeniasis, the elimination of the infection in both pigs and humans can also be achieved. CONCLUSIONS: Our mathematical model has the potential for planning, and designing effective intervention strategies including both mass vaccination and/or chemotherapeutic treatment to eliminate pig cysticercosis, human taeniasis and human neurocysticercosis. The model can be adapted to any given community with mild, moderate endemicity, or even in hyperendemic regions.

Mathematical model of the life cycle of taenia-cysticercosis: transmission dynamics and chemotherapy (Part 1).

BACKGROUND: Taenia solium is the aetiological agent of human taeniasis, pig cysticercosis and human neurocysticercosis, which are serious public health problems, especially in developing countries. METHODS: A mathematical model of the transmission dynamics of taeniasis-cysticercosis is formulated. The model consists of a coupled system of differential equations, which are density-dependent equations for describing the flow of the parasite through the life cycle. The model is hybrid since it comprises deterministic equations with stochastic elements which describe changes in the mean parasite burden and incorporates the overall pattern of the parasites' distribution. RESULTS: Sensitivity and bifurcation analyses were carried out to determine the range of values of the model. The model can reproduce the observed epidemiological patterns of human taeniasis, pig and human cysticercosis. For example, for a wide range of parameter values, the mean intensity of adult worms tends to rapidly stabilize in one parasite per individual host. From this model, we also derived a Susceptible-Infected model to describe the prevalence of infection in humans and pigs. Chemotherapeutic interventions against pig cysticercosis or human taeniasis may reduce rapidly and effectively the mean intensity of human taeniasis, pig cysticercosis and human cysticercosis. This effect can be achieved even if the protective efficacy of the drug is of the order of 90% and the coverage rate is 90%. This means that health in humans infected either with adult worms or cysticerci may be achieved by the application of anthelmintic drugs against pig cysticercosis. However, treatment against human cysticercosis alone, does not influence neither human teniasis nor pig cysticercosis. This is because human cysticercosis infection does not influence the value of the basic reproductive number (Ro). CONCLUSIONS: Even coverage of 100% in the administration of anthelmintics did not eliminate the infection. Then elimination of the infection in all hosts does not seem a feasible goal to achieve by administering only chemotherapeutic interventions. Throughout the manuscript a discussion of our model in the context of other models of taeniasis-cysticercosis is presented.

Multivariate Entropy Characterizes the Gene Expression and Protein-Protein Networks in Four Types of Cancer.

There is an important urgency to detect cancer at early stages to treat it, to improve the patients' lifespans, and even to cure it. In this work, we determined the entropic contributions of genes in cancer networks. We detected sudden changes in entropy values in melanoma, hepatocellular carcinoma, pancreatic cancer, and squamous lung cell carcinoma associated to transitions from healthy controls to cancer. We also identified the most relevant genes involved in carcinogenic process of the four types of cancer with the help of entropic changes in local networks. Their corresponding proteins could be used as potential targets for treatments and as biomarkers of cancer.

The genome project of Taenia solium.

We have constituted a consortium of key laboratories at the National Autonomous University of Mexico to carry out a genomic project for Taenia solium. This project will provide powerful resources for the study of taeniasis/cysticercosis, and, in conjunction with the Echinococcus granulosus and Echinococcus multilocularis genome project of expressed sequence tags (ESTs), will mark the advent of genomics for cestode parasites. Our project is planned in two consecutive stages. The first stage is being carried out to determine some basic parameters of the T. solium genome. Afterwards, we will evaluate the best strategy for the second stage, a full blown genome project. We have estimated the T. solium genome size by two different approaches: cytofluorometry on isolated cyton nuclei, as well as a probabilistic calculation based on approximately 2000 sequenced genomic clones, approximately 3000 ESTs, resulting in size estimates of 270 and 251 Mb, respectively. In terms of sequencing, our goal for the first stage is to characterize several thousand EST's (from adult worm and cysticerci cDNA libraries) and genomic clones. Results obtained so far from about 16,000 sequenced ESTs from the adult stage, show that only about 40% of the T. solium coding sequences have a previously sequenced homologue. Many of the best hits are found with mammalian genes, especially with humans. However, 1.5% of the hits lack homologues in humans, making these genes immediate candidates for investigation on pharmaco-therapy, diagnostics and vaccination. Most T. solium ESTs are related to gene regulation, and signal transduction. Other important functions are housekeeping, metabolism, cell division, cytoskeleton, proteases, vacuolar transport, hormone response, and extracellular matrix activities. Preliminary results also suggest that the genome of T. solium is not highly repetitive.

Prevalence of infection, mean worm burden and degree of worn aggregation as determinants of prevalence of disease due to intestinal helminths

Theoretical predictions of disease prevalence due to helminth infections based upon a simple probabilistica model which considers the infection prevalence, the mean worm urden and the degree of worm aggregation are presented. A numerical reappraisal of the likely estimates of the degree of aggregation based upon maximun likelihood estimates of the negative binomial distribution is presented. The prevalence of disease shows a positive relationship with the mean worm burden. This association is hyperbolic when helminth parasites are severely aggregated but is s-shaped when helminth parasites tend to be oversidpersed. The prevalence of disease decreases with the degree of worm aggregation whem the values of the mean intensity are low; as the mean intensity increases this association becomes positive. The relationship between prevalence of disease and prevalence of infection is hyperbolic for severe degrees of parasite aggregation and is s-shaped for intermediate degrees of aggregation. However, if the mean intesnsity is low and the degree of aggreation is high there could be a negative raltionship between the prevalence of disease due to helminth parasites is feasible for determined ranges of values of the infection prevalence, mena intensity and the degree of worm clumping

El grado de agregación de Ascaris lumbricoides según grupos de edad, después de una intervención antihelmíntica de masas / The degree of age-aggregation of Ascaris lumbricoides in a community after a mass antihelminthic intervention

Objetivo. Descubrir la heterogeneidad de la reinfección por Ascaris lumbricoides según grupos de edad, en distintos intervalos, después de un primer tratamiento antihelmíntico masivo. Material y métodos. A partir de datos de la prevalencia e intensidad de la infección por A. lumbricoides obtenidos en un estudio epidemiológico de ascariasis, realizado en Coatzacoalcos, Veracruz, México, se deriva el grado de agregación por medio del método de máxima verosimilitud, asumiendo una distribución binomial negativa del parásito en el huésped. Resultados. Se muestra que la distribución del parásito en el huésped es distinta en el ámbito poblacional que en el de grupos de edad, que la recuperación de la infección no es uniforme; y que la dinámica de asociación huésped-parásito exhibe una marcada desestabilización de su equilibrio endémico después de una primera intervención de masas. Conclusiones. Lo anterior sugiere que existe una alta variabilidad en la agregación entre los distintos grupos de edad y, por tanto, la infección y la reinfección son heterogéneas respecto a la edad. Después de la desestabilización del equilibrio endémico, los estados que alcanza el sistema huésped-parásito son transitorios. Dada la heterogeneidad de la infección, los tratamientos selectivos parecen ser la estrategia más adecuada para disminuirla

Objective. The degree of aggregation is determined for the whole population and for different age-specific strata and is used for assessing the reinfection rate after a mass antihelminthic chemotherapeutic intervention. Material and methods. The degree of aggregation of Ascaris lumbricoides is derived from prevalence and intensity of infection data obtained from an epidemiological study of ascariasis carried out in Coatzacoalcos, Veracruz, México by means of maximum likelihood estimation of the negative binomial distribution. Results. The results show that the distribution of the parasite for the whole population differs from the distribution of the parasite within each age-specific stratum; the reinfection rate is not uniform; the dynamics of the hostparasite association exhibits a clear destabilization of its endemic equilibrium after a first round of mass treatment.Conclusions. It is suggested that the aggregation among the different age-groups is highly variable and hence the infection and reinfection rates are heterogeneous with regard to age; these states of the host-parasite system are transient. Given the heterogeneity of the infection, the selective treatment seems to be the most adequate strategy to diminish helminth infection rates.

Nociones básicas de la dinámica de poblaciones del SIDA / Basic elements of the population dynamics of AIDS

En este trabajo se presentan los elementos básicos de los modelos matemáticos sobre la dinámica de poblaciones del SIDA con los que se pueden hacer predicciones sobre el curso de la epidemia a largo plazo. El umbral de la epidemia puede calcularse a partir del coeficiente de variación de la distribución de la actividad sexual y/o, en forma aproximada, como la suma del período de incubación más la duración de la infecciosidad