Efficacy and safety of glecaprevir/pibrentasvir in treatment-naïve adults with chronic hepatitis C virus genotypes 1–6 in Brazil

Introduction and objectives: Glecaprevir/pibrentasvir is a highly effective and well tolerated treatment for hepatitis C infection. Brazilian patients were not included in the original development studies for glecaprevir/pibrentasvir. This study aimed to assess safety and efficacy of glecaprevir/pibrentasvir in treatment-naïve Brazilian adults without cirrhosis or with compensated cirrhosis. Patients and methods: EXPEDITION-3 was a Phase 3, open-label, multicenter study in treatment-naïve Brazilian adults with hepatitis C infection genotype 1–6. Patients without cirrhosis (F2 or F3) or with compensated cirrhosis (F4) received 8 or 12 weeks of glecaprevir/pibrentasvir, respectively. The primary efficacy endpoint was the rate of sustained virologic response at post-treatment Week 12. Secondary endpoints were on-treatment virologic failure and relapse rates. Baseline polymorphisms were assessed in NS3 and NS5A. Adverse events and laboratory abnormalities were monitored. Results: 100 patients were enrolled, 75 received 8 weeks of treatment and 25 received 12 weeks; all patients completed treatment. Overall sustained virologic response at post-treatment Week 12 rate was high (98.0%; 98/100; 95% confidence interval: 93.0–99.4) and remained high regardless of baseline viral or host factors, including demographics, hepatitis C virus RNA levels, polymorphisms in NS3 and/or NS5A, genotype, and relevant comorbidities. 55% of patients reported ≥1 adverse event, the most common beingheadache (18.0%). Four patients reported serious adverse events; none were considered drug related orled to study drug discontinuation. No hepatic decompensations were observed.Conclusions: Glecaprevir/pibrentasvir was effective and well tolerated in treatment-naïve Brazilianpatients with hepatitis C infection without cirrhosis and with compensated cirrhosis

Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells

The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell–microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities of SLRP in response to CSC enrichment, simultaneously acquiring TMZ resistance, cellular heterogeneity, and a quiescent phenotype, suggesting a novel pivotal role for SLRP in drug resistance and cell plasticity of CSC-like, allowing cell survival and ECM/niche modulation potential.This study was supported by Fundació la Marató TV3, Project n° 111431

¿Qué es la gramaticografía? Maestros, proyectos, estudios

Il volume presenta la grammaticografia come disciplina storiografica, cos'è, a cosa serve, chi sono i suoi maestri, quali sono i progetti attuali più importanti e quali sono i modelli di articoli più frequenti.The volume presents grammarography as a discipline of historiography, what it is, what it is for, who are its masters, what are the most important current projects and what are the most frequent models of study.El volumen presenta la gramaticografía como disciplina de la historiografía, qué es, para qué sirve, quiénes son sus maestros, cuáles son los proyectos actuales más importantes y cuáles son los modelos de estudios más frecuentes

Size-segregated chemical composition of aerosol emissions in an urban road tunnel in Portugal

An atmospheric aerosol study was performed in 2008 inside an urban road tunnel, in Lisbon, Portugal. Using a high volume impactor, the aerosol was collected into four size fractions (PM0.5, PM0.5–1, PM1–2.5 and PM2.5–10) and analysed for particle mass (PM), organic and elemental carbon (OC and EC), polycyclic aromatic hydrocarbons (PAH), soluble inorganic ions and elemental composition. Three main groups of compounds were discriminated in the tunnel aerosol: carbonaceous, soil component and vehicle mechanical wear. Measurements indicate that Cu can be a good tracer for wear emissions of road traffic. Cu levels correlate strongly with Fe, Mn, Sn and Cr, showing a highly linear constant ratio in all size ranges, suggesting a unique origin through sizes. Ratios of Cu with other elements can be used to source apportion the trace elements present in urban atmospheres, mainly on what concerns coarse aerosol particles.Fundação para a Ciência e a Tecnologia (FCT

EGFR wild-type amplification and activation promote invasion and development of glioblastoma independent of angiogenesis

Angiogenesis is regarded as a hallmark of cancer progression and it has been postulated that solid tumor growth depends on angiogenesis. At present, however, it is clear that tumor cell invasion can occur without angiogenesis, a phenomenon that is particularly evident by the infiltrative growth of malignant brain tumors, such as glioblastomas (GBMs). In these tumors, amplification or overexpression of wild-type (wt) or truncated and constitutively activated epidermal growth factor receptor (EGFR) are regarded as important events in GBM development, where the complex downstream signaling events have been implicated in tumor cell invasion, angiogenesis and proliferation. Here, we show that amplification and in particular activation of wild-type EGFR represents an underlying mechanism for non-angiogenic, invasive tumor growth. Using a clinically relevant human GBM xenograft model, we show that tumor cells with EGFR gene amplification and activation diffusely infiltrate normal brain tissue independent of angiogenesis and that transient inhibition of EGFR activity by cetuximab inhibits the invasive tumor growth. Moreover, stable, long-term expression of a dominant-negative EGFR leads to a mesenchymal to epithelial-like transition and induction of angiogenic tumor growth. Analysis of human GBM biopsies confirmed that EGFR activation correlated with invasive/non-angiogenic tumor growth. In conclusion, our results indicate that activation of wild-type EGFR promotes invasion and glioblastoma development independent of angiogenesis, whereas loss of its activity results in angiogenic tumor growth. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-013-1101-1) contains supplementary material, which is available to authorized users