Coexistence of three EGFR mutations in an NSCLC patient: A brief report

The epidermal growth factor receptor (EGFR) represents a molecular target for tyrosine kinase inhibitors for non-small cell lung cancer (NSCLC) patients with a mutation in the EGFR gene. Mutations of the EGFR gene that occur at a single position in NSCLC tissue are found as single, whereas two or more mutations on the same allele are poorly detected and investigated

HDAC inhibition is associated to valproic acid induction of early megakaryocytic markers

Valproic acid (VPA), a histone deacetylase inhibitor, causes differentiation in different cell lines and in a cell-specific manner; yet, its effect on megakaryocytic (MK) differentiation has not been studied. We evaluated whether VPA induces MK differentiation in a UT-7 cell line through histone acetylation in the GpIIIa gene region and activation of the ERK pathway. UT-7 cells, derived from megakaryoblastic leukemia, were treated with VPA at various concentrations, and the expression of differentiation markers as well as the gene expression profile was assessed. Flow cytometry, immunoblot analysis, and RT-PCR demonstrated that VPA induced the expression of the early MK markers GpIIIa (CD61) and GpIIb/IIIa (CD41) in a dose-dependent manner. The VPA-treated cells showed hyperacetylation of the histones H3 and H4; in particular, histone acetylation was found to have been associated with CD61 expression, in that the GpIIIa promoter showed H4 hyperacetylation, as demonstrated by the chromatin immunoprecipitation assay. Furthermore, activation of the ERK pathway was involved in VPA-mediated CD61/CD41 expression and in cell adhesion, as demonstrated by using the MEK/ERK inhibitor U0126. In conclusion, the capacity of VPA to commit UT-7 cells to MK differentiation is mediated by its inhibitory action on HDAC and the long-lived activation of ERK1/2

Key role of MEK/ERK pathway in sustaining tumorigenicity and in vitro radioresistance of embryonal rhabdomyosarcoma stem-like cell population

The identification of signaling pathways that affect the cancer stem-like phenotype may provide insights into therapeutic targets for combating embryonal rhabdomyosarcoma. The aim of this study was to investigate the role of the MEK/ERK pathway in controlling the cancer stem-like phenotype using a model of rhabdospheres derived from the embryonal rhabdomyosarcoma cell line (RD)

ERP signs of categorical and supra-categorical processing of visual information

Background: The aim of the present study was to investigate to what extent shared and distinct brain mechanisms are possibly subserving the processing of visual supra-categorical and categorical knowledge as observed with event-related potentials of the brain. Access time to these knowledge types was also investigated. Picture pairs of animals, objects, and mixed types were presented. Participants were asked to decide whether each pair contained pictures belonging to the same category (either animals or man-made objects) or to different categories by pressing one of two buttons. Response accuracy and reaction times (RTs) were also recorded. Results: Both ERPs and RTs were grand-averaged separately for the same-different supra-categories and the animal-object categories. Behavioral performance was faster for more endomorphic pairs, i. e., animals vs. objects and same vs. different category pairs. For ERPs, a modulation of the earliest C1 and subsequent P1 responses to the same vs. different supra-category pairs, but not to the animal vs. object category pairs, was found. This finding supports the view that early afferent processing in the striate cortex can be boosted as a by-product of attention allocated to the processing of shapes and basic features that are mismatched, but not to their semantic quintessence, during same-different supra-categorical judgment. Most importantly, the fact that this processing accrual occurred independent of a traditional experimental condition requiring selective attention to a stimulus source out of the various sources addressed makes it conceivable that this processing accrual may arise from the attentional demand deriving from the alternate focusing of visual attention within and across stimulus categorical pairs' basic structural features. Additional posterior ERP reflections of the brain more prominently processing animal category and same-category pairs were observed at the N1 and N2 levels, respectively, as well as at a late positive complex level, overall most likely related to different stages of analysis of the greater endomorphy of these shape groups. Conversely, an enhanced fronto-central and fronto-lateral N2 as well as a centro-parietal N400 to man-made objects and different-category pairs were found, possibly indexing processing of these entities' lower endomorphy and isomorphy at the basic features and semantic levels, respectively. Conclusion: Overall, the present ERP results revealed shared and distinct mechanisms of access to supra-categorical and categorical knowledge in the same way in which shared and distinct neural representations underlie the processing of diverse semantic categories. Additionally, they outlined the serial nature of categorical and supra-categorical representations, indicating the sequential steps of access to these separate knowledge types. (C) 2014 Elsevier B.V. All rights reserved

Frailty trajectories in ICU survivors: A comparison between the clinical frailty scale and the Tilburg frailty Indicator and association with 1 year mortality

Purpose: To test the agreement of the Clinical Frailty Scale (CFS) and the Tilburg Frailty Indicator (TFI), their association with 3, 6 months and 1-year mortality and the trajectory of frailty in a mixed population of ICU survivors. Material and methods: This is a prospective, multicenter, longitudinal study on ICU survivors ≥18 years old with an ICU stay >72 h. For each patient, sociodemographic and clinical data were collected. Frailty was assessed during ICU stay and at 3, 6, 12 months after ICU discharge, through both CFS and TFI. Results: 124 patients with a mean age of 66 years old were enrolled. The baseline prevalence of frailty was 15.3% by CFS and 44.4% by TFI. Baseline CFS and TFI correlated but showed low agreement (Cohen's K = 0.23, p < 0.001). Baseline CFS score, but not TFI, was significantly associated to 1 year mortality. Moreover, CFS score during the follow-up was independently associated 1-year mortality (OR = 1.43; 95% CI: 1.18-1.73). Conclusions: CFS and TFI identify different populations of frail ICU survivors. Frail patients before ICU according to CFS have a significantly higher mortality after ICU discharge. The CFS during follow-up is an independent negative prognostic factor of long-term mortality in the ICU population

DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action

During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs

Changes in Extracellular Matrix in Subcutaneous Small Resistance Arteries of Patients with Primary Aldosteronism

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Tuning of photonic crystal cavities by controlled removal of locally infiltrated water

We present a spectral tuning mechanism of photonic crystal microcavities based on microfluidics. The microinfiltration with water of one or few cavity holes and its subsequent controlled evaporation allow us to tune the cavity resonances in a spectral range larger than 20 nm, with subnanometer accuracy, and we also observe that the addition of water in the microcavity region improves its quality factor Q. (C) 2009 American Institute of Physics. [doi:10.1063/1.3247894

Environmental distribution of Cryptococcus neoformans and Cryptococcus gattii around the Mediterranean basin

In order to elucidate the distribution of Cryptococcus neoformans and C. gattii in the Mediterranean basin, an extensive environmental survey was carried out during 2012-15. A total of 302 sites located in 12 countries were sampled, 6436 samples from 3765 trees were collected, and 5% of trees were found to be colonized by cryptococcal yeasts. Cryptococcus neoformans was isolated from 177 trees and C. gattii from 13. Cryptococcus neoformans colonized 27% of Ceratonia, 10% of Olea, Platanus and Prunus trees and a lower percentage of other tree genera. The 13 C. gattii isolates were collected from five Eucalyptus, four Ceratonia, two Pinus, and two Olea trees. C. neoformans was distributed all around the Mediterranean basin, whereas C. gattii was isolated in Greece, Southern Italy, and Spain, in agreement with previous findings from both clinical and environmental sources. Among C. neoformans isolates VNI was the prevalent molecular type but VNII, VNIV and VNIII hybrid strains were also isolated. With the exception of a single VGIV isolate, all C. gattii isolates were VGI. The results confirmed the presence of both Cryptococcus species in the Mediterranean environment, and showed that both carob and olive trees represent animportant niche for these yeasts