Value of polymorphisms and DNA methylation for the expression of CYP2E1 enzyme: implications in pharmacogenomics

Different individuals possess slightly different genetic information and show genetically-determined differences in several enzyme activities due to genetic variability. Following an integrated approach, we studied the polymorphisms and DNA methylation of the 5′ flanking region of the metabolizing enzyme CYP2E1 in correlation to its expression in both tumor and non-neoplastic liver cell lines, since to date little is known about the influence of these (epi)genetic elements in basal conditions and under induction by the specific inductor and a demethylating agent. In treated cells, reduced DNA methylation, assessed both at genomic and gene level, was not consistently associated with the increase of enzyme expression. Interestingly, the Rsa/Pst haplotype differentially influenced CYP2E1 enzyme expression. In addition, regarding the Variable Number of Tandem Repeats polymorphism, cells with A4/A4 genotype showed a greater expression inhibition (ranging from 20% to 30%) compared with others carrying the A2/A2 one, while those cells bringing A2/A3 genotype showed an increase of expression (of 25%, about). Finally, we demonstrated for the first time that the A2 and A3 CYP2E1 alleles play a more important role in the expression of the enzyme, compared with other (epi)genetic factors, since they are binding sites for trans-acting proteins. In conclusion our data contributes to define a hypothetical model of regulation of the expression of this enzyme. Clarifying the complex regulation of CYP2E1 enzyme expression, either by genetic or epigenetic elements, will give useful topics in pharmacogenomics, for typing people regarding its metabolizing capability and therapy response

CYP2E1 VNTR genotyping associated to anti\u2013tuberculosis drug-induced hepatotoxicity

Tuberculosis (TB) remains a major worldwide health problem with an estimated of 9.0 million of new cases and 1.5 million of deaths in 2013. Anti\u2013TB drug-induced hepatotoxicity (ATDH) is considered the most serious and prevalent adverse drug reaction in TB treatment. Isoniazid (INH), one of the first-line drugs against TB, is more commonly associated to ATDH and, it is well known that the enzyme Citochrome P450 2E1 (CYP2E1) is involved in INH metabolism. It has been found that variable number tandem repeat (VNTR) polymorphic sequences in the promoter region regulate negatively CYP2E1 gene transcription: consequently, it could be put in relationship with adverse TB-drugs reactions. In this report we for the first time show advanced investigations regarding the association between CYP2E1- VNTR and ATDH; the study started last year also thank to a small grant by CUIA but was widely extended with other funds. We studied genotypic frequency distributions of the CYP2E1-VNTR (using PCR-RFLP methodology) in a cohort 294 TB patients treated with anti-TB drugs: 167 were Argentines (130 controls without ATDH and 37 cases with ATDH) and 127 were Bolivians (83 controls without ATDH and 44 cases with ATDH). Chi-squared test was used to compare proportions: a value of P<0.05 was considered to be statistically significant. In the Argentine population, we observed that the A2/A4 genotype frequency was significantly higher in cases than in controls (P=0.048). In contrast, no significant differences were observed in Bolivian population between controls and cases regarding to distribution of VNTR genotypes. Our preliminary results showed that the presence of A4 allele of CYP2E1-VNTR could be associated to ATDH, at least in the Argentine population. These results are in agreement with previously reported data which proposed that the transcriptional activity of A4 allele was higher than that of A2 allele since the transcriptional suppression of A4 was weaker than that of A2. It will be necessary to increase the number of cases in both populations to confirm this possible and interesting association. The CYP2E1 VNTR genotype, in fact, promises to be an attractive marker that could be used to predict or prevent ATDH like the acetylator profile

Exploring Multiple‐discreteness in Freight Transport. A Multiple Discrete Extreme Value Model Application for Grain Consolidators in Argentina

There are some examples where freight choices may be of a multiple discrete nature, especially the ones at more tactical levels of planning. Nevertheless, this has not been investigated in the literature, although several discrete-continuous models for mode/vehicle type and shipment size choice have been developed in freight transport. In this work, we propose that the decision of port and mode of the grain consolidators in Argentina is of a discrete-continuous nature, where they can choose more than one alternative and how much of their production to send by each mode. The Multiple Discrete Extreme Value Model (MDCEV) framework was applied to a stated preference data set with a response variable that allowed this multiple-discreteness. To our knowledge, this is the only application of the MDCEV in regional freight context. Free alongside ship price, freight transport cost, lead-time and travel time were included in the utility function and observed and random heterogeneity was captured by the interaction with the consolidator’s characteristics and random coefficients. In addition, different discrete choice models were used to compare the forecasting performance, willingness to pay measures and structure of the utility function against

Quintais agroecológicos conquistam o Semiárido brasileiro: Segurança alimentar para os mais vulneráveis com o uso da força da terra

Quintais representam um espaço para prosa, troca de mudas e descanso; o projeto acrescentou a estes fatores a utilização de princípios agroecológicos. O resultado é um sistema que possibilita a produção de alimentos saudáveis a partir de processos produtivos coerentes com os recursos naturais disponíveis

Strong field gravitational lensing in scalar tensor theories

Strong field gravitational lensing in the Brans-Dicke theory has been studied. The deflection angle for photons passing very close to the photon sphere is estimated for the static spherically symmetric space-time of the theory and the position and magnification of the relativistic images are obtained. Modeling the super massive central object of the galaxy by the Brans-Dicke space-time, numerical values of different strong lensing observable are estimated. It is found that against the expectation there is no significant scalar field effect in the strong field observable lensing parameters. This observation raises question on the potentiality of the strong field lensing to discriminate different gravitational theories.Comment: 20 pages, accepted in Class. Quantum Grav., final versio

Geometrothermodynamics of the Kehagias-Sfetsos Black Hole

The application of information geometric ideas to statistical mechanics using a metric on the space of states, pioneered by Ruppeiner and Weinhold, has proved to be a useful alternative approach to characterizing phase transitions. Some puzzling anomalies become apparent, however, when these methods are applied to the study of black hole thermodynamics. A possible resolution was suggested by Quevedo et al. who emphasized the importance of Legendre invariance in thermodynamic metrics. They found physically consistent results for various black holes when using a Legendre invariant metric, which agreed with a direct determination of the properties of phase transitions from the specific heat. Recently, information geometric methods have been employed by Wei et al. to study the Kehagias-Sfetsos (KS) black hole in Horava-Lifshitz gravity. The formalism suggests that a coupling parameter in this theory plays a role analogous to the charge in Reissner-Nordstrom (RN) black holes or angular momentum in the Kerr black hole and calculation of the specific heat shows a singularity which may be interpreted as a phase transition. When the curvature of the Ruppeiner metric is calculated for such a theory it does not, however, show a singularity at the phase transition point. We show that the curvature of a particular Legendre invariant ("Quevedo") metric for the KS black hole is singular at the phase transition point. We contrast the results for the Ruppeiner, Weinhold and Quevedo metrics and in the latter case investigate the consistency of taking either the entropy or mass as the thermodynamic potential.Comment: v2: some references adde

An International Perspective on Chronic Multimorbidity: Approaching the Elephant in the Room

Multimorbidity is a common and burdensome condition that may affect quality of life, increase medical needs, and make people live more years of life with disability. Negative outcomes related to multimorbidity occur beyond what we would expect from the summed effect of single conditions, as chronic diseases interact with each other, mutually enhancing their negative effects, and eventually leading to new clinical phenotypes. Moreover, multimorbidity mirrors an accelerated global susceptibility and a loss of resilience, which are both hallmarks of aging. Due to the complexity of its assessment and definition, and the lack of clear evidence steering its management, multimorbidity represents one of the main current challenges for clinicians, researchers, and policymakers. The authors of this article recently reflected on these issues during two twin international symposia at the 2016 European Union Geriatric Medicine Society (EUGMS) meeting in Lisbon, Portugal, and the 2016 Gerontological Society of America (GSA) meeting in New Orleans, USA. The present work summarizes the most relevant aspects related to multimorbidity, with the ultimate goal to identify knowledge gaps and suggest future directions to approach this condition

Cell Membrane-Coated Magnetic Nanocubes with a Homotypic Targeting Ability Increase Intracellular Temperature due to ROS Scavenging and Act as a Versatile Theranostic System for Glioblastoma Multiforme

In this study, hybrid nanocubes composed of magnetite (Fe3O4) and manganese dioxide (MnO2), coated with U-251 MG cell-derived membranes (CM-NCubes) are synthesized. The CM-NCubes demonstrate a concentration-dependent oxygen generation (up to 15%), and, for the first time in the literature, an intracellular increase of temperature (6 \ub0C) due to the exothermic scavenging reaction of hydrogen peroxide (H2O2) is showed. Internalization studies demonstrate that the CM-NCubes are internalized much faster and at a higher extent by the homotypic U-251 MG cell line compared to other cerebral cell lines. The ability of the CM-NCubes to cross an in vitro model of the blood-brain barrier is also assessed. The CM-NCubes show the ability to respond to a static magnet and to accumulate in cells even under flowing conditions. Moreover, it is demonstrated that 500 \ub5g mL 121 of sorafenib-loaded or unloaded CM-NCubes are able to induce cell death by apoptosis in U-251 MG spheroids that are used as a tumor model, after their exposure to an alternating magnetic field (AMF). Finally, it is shown that the combination of sorafenib and AMF induces a higher enzymatic activity of caspase 3 and caspase 9, probably due to an increment in reactive oxygen species by means of hyperthermia

Black Holes in Ho\v{r}ava Gravity with Higher Derivative Magnetic Terms

We consider Horava gravity coupled to Maxwell and higher derivative magnetic terms. We construct static spherically symmetric black hole solutions in the low-energy approximation. We calculate the horizon locations and temperatures in the near-extremal limit, for asymptotically flat and (anti-)de Sitter spaces. We also construct a detailed balanced version of the theory, for which we find projectable and non-projectable, non-perturbative solutions.Comment: 17 pages. v2: Up to date with published version; some minor remarks and more reference