Parthenolide induces rapid thiol oxidation that leads to ferroptosis in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is both a devastating and common disease. Every year in the United States, about 24,500 men and 10,000 women are diagnosed with HCC, and more than half of those diagnosed patients die from this disease. Thus far, conventional therapeutics have not been successful for patients with HCC due to various underlying comorbidities. Poor survival rate and high incidence of recurrence after therapy indicate that the differences between the redox environments of normal surrounding liver and HCC are valuable targets to improve treatment efficacy. Parthenolide (PTL) is a naturally found therapeutic with anti-cancer and anti-inflammatory properties. PTL can alter HCC’s antioxidant environment through thiol modifications leaving tumor cells sensitive to elevated reactive oxygen species (ROS). Investigating the link between altered thiol mechanism and increased sensitivity to iron-mediated lipid peroxidation will allow for improved treatment of HCC. HepG2 (human) and McARH7777 (rat) HCC cells treated with PTL with increasing concentrations decrease cell viability and clonogenic efficiency in vitro. PTL increases glutathione (GSH) oxidation rescued by the addition of a GSH precursor, N-acetylcysteine (NAC). In addition, this elevation in thiol oxidation results in an overall increase in mitochondrial dysfunction. To elucidate if cell death is through lipid peroxidation, using a lipid peroxidation sensor indicated PTL increases lipid oxidation levels after 6 h. Additionally, western blotting reveals glutathione peroxidase 4 (GPx4) protein levels decrease after treatment with PTL suggesting cells are incapable of preventing lipid peroxidation after exposure to PTL. An elevation in lipid peroxidation will lead to a form of cell death known as ferroptosis. To further establish ferroptosis as a critical mechanism of death for HCC in vitro, the addition of ferrostatin-1 combined with PTL demonstrates a partial recovery in a colony survival assay. This study reveals that PTL can induce tumor cell death through elevations in intracellular oxidation, leaving cells sensitive to ferroptosis

Thinking outside the curve, part I: modeling birthweight distribution

<p>Abstract</p> <p>Background</p> <p>Greater epidemiologic understanding of the relationships among fetal-infant mortality and its prognostic factors, including birthweight, could have vast public health implications. A key step toward that understanding is a realistic and tractable framework for analyzing birthweight distributions and fetal-infant mortality. The present paper is the first of a two-part series that introduces such a framework.</p> <p>Methods</p> <p>We propose describing a birthweight distribution via a normal mixture model in which the number of components is determined from the data using a model selection criterion rather than fixed <it>a priori</it>.</p> <p>Results</p> <p>We address a number of methodological issues, including how the number of components selected depends on the sample size, how the choice of model selection criterion influences the results, and how estimates of mixture model parameters based on multiple samples from the same population can be combined to produce confidence intervals. As an illustration, we find that a 4-component normal mixture model reasonably describes the birthweight distribution for a population of white singleton infants born to heavily smoking mothers. We also compare this 4-component normal mixture model to two competitors from the existing literature: a contaminated normal model and a 2-component normal mixture model. In a second illustration, we discover that a 6-component normal mixture model may be more appropriate than a 4-component normal mixture model for a general population of black singletons.</p> <p>Conclusions</p> <p>The framework developed in this paper avoids assuming the existence of an interval of birthweights over which there are no compromised pregnancies and does not constrain birthweights within compromised pregnancies to be normally distributed. Thus, the present framework can reveal heterogeneity in birthweight that is undetectable via a contaminated normal model or a 2-component normal mixture model.</p

Two naphthalene degrading bacteria belonging to the genera Paenibacillus and Pseudomonas isolated from a highly polluted lagoon perform different sensitivities to the organic and heavy metal contaminants

Two bacterial strains were isolated in the presence of naphthalene as the sole carbon and energy source from sediments of the Orbetello Lagoon, Italy, which is highly contaminated with both organic compounds and metals. 16S rRNA gene sequence analysis of the two isolates assigned the strains to the genera Paenibacillus and Pseudomonas. The effect of different contaminants on the growth behaviors of the two strains was investigated. Pseudomonas sp. ORNaP2 showed a higher tolerance to benzene, toluene, and ethylbenzene than Paenibacillus sp. ORNaP1. In addition, the toxicity of heavy metals potentially present as co-pollutants in the investigated site was tested. Here, strain Paenibacillus sp. ORNaP1 showed a higher tolerance towards arsenic, cadmium, and lead, whereas it was far more sensitive towards mercury than strain Pseudomonas sp. ORNaP2. These differences between the Gram-negative Pseudomonas and the Gram-positive Paenibacillus strain can be explained by different general adaptive response systems present in the two bacteria

The computation of the geoid model in the state of São Paulo using two methodologies and GOCE models

The purpose of this manuscript is to compute and to evaluate the geoid model in the State of São Paulo from two methodologies (Stokes' integral through the Fast Fourier Transform - FFT and Least Squares Collocation - LSC). Another objective of this study is to verify the potentiality of GOCE-based. A special attention is given to GOCE mission. The theory related to Stokes' integral and Least Squares Collocation is also discussed in this work. The spectral decomposition was employed in the geoid models computation and the long wavelength component was represented by EGM2008 up to degree and order 150 and 360 and GOCE-based models up to 150. The models were compared in terms of geoid height residual and absolute and relative comparisons from GPS/leveling and the results show consistency between them. In addition, a comparison in the mountain regions was carried out to verify the methodologies behavior in this area; the results showed that LSC is less consistent than FFT

Il diritto aeronautico: profili storici e caratteri.

Lo scritto tratta degli aspetti evolutivi e storici del quadro normativo dedicato al sistema aviatorio ripercorrendo il fenomeno dalla sua genesi come fenomeno pionieristico alla comparse dei primi interventi normativi in materia. Espone rapidamente l\u2019evoluzione del settore accennando agli interventi regolamentativi degli anni quaranta e di inizio del nuovo millennio

Il volo da diporto o sportivo

In questo scritto viene analizzato, dal punto di vista giuridico, il volo da diporto o sportivo ovvero l\u2019attivit\ue0 aeronautica effettuata per finalit\ue0 non lucrative. La materia \ue8 stata oggetto di una riforma radicale, dal punto di vista normativo, che ha sostanzialmente modificato la stessa classificazione giuridica dei mezzi, con rilevanti ricadute in tema di sanzioni anche penali. L\u2019analisi evolve quindi, in virt\uf9 della specialit\ue0 della materia, dalla trattazione delle fonti giuridiche del fenomeno alla classificazione degli apparecchi ed alle relative modifiche introdotte dalle innovazioni normative. Vengono infine sviscerati alcuni aspetti di criticit\ue0 propri dell\u2019assetto giuridico della materia

L'aeromobile

Lo scritto affronta il sistema classificatorio del bene principe della navigazione aerea, ovvero l\u2019aeromobile. L\u2019esposizione tratta della qualifica del bene stesso, della sua individuazione, delle specificit\ue0 relative alla disciplina della registrazione come bene mobile registrato e delle relative ripercussioni sia dal punto di vista privatistico che pubblicistico. Prosegue poi con l\u2019analisi della documentazione che accompagna in ogni momento l\u2019aeromobile, delle procedure per la sua costruzione e la sua distruzione. Al termine della trattazione vengono esaminate, anche con impronta comparatistica le nuove tipologie ti apparecchi, ovvero i velivoli senza pilota e i velivoli ultraleggeri recentemente inseriti nella qualifica di aeromobile