Sunitinib in metastatic renal cell carcinoma: The pharmacological basis of the alternative 2/1 schedule

No abstract availabl

SMAD4 loss enables EGF, TGF\u3b21 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells

Epidermal Growth Factor (EGF) receptor overexpression, KRAS, TP53, CDKN2A and SMAD4 mutations characterize pancreatic ductal adenocarcinoma. This mutational landscape might influence cancer cells response to EGF, Transforming Growth Factor \u3b21 (TGF\u3b21) and stromal inflammatory calcium binding proteins S100A8/A9. We investigated whether chronic exposure to EGF modifies in a SMAD4-dependent manner pancreatic cancer cell signalling, proliferation and invasion in response to EGF, TGF\u3b21 and S100A8/A9. BxPC3, homozigously deleted (HD) for SMAD4, and BxPC3-SMAD4+ cells were or not stimulated with EGF (100 ng/mL) for three days. EGF pre-treated and non pretreated cells were stimulated with a single dose of EGF (100 ng/mL), TGF\u3b21 (0,02 ng/mL), S100A8/A9 (10 nM). Signalling pathways (Reverse Phase Protein Array and western blot), cell migration (Matrigel) and cell proliferation (XTT) were evaluated. SMAD4 HD constitutively activated ERK and Wnt/\u3b2-catenin, while inhibiting PI3K/AKT pathways. These effects were antagonized by chronic EGF, which increased p-BAD (anti-apoptotic) in response to combined TGF\u3b21 and S100A8/A9 stimulation. SMAD4 HD underlied the inhibition of NF-\u3baB and PI3K/AKT in response to TGF\u3b21 and S100A8/A9, which also induced cell migration. Chronic EGF exposure enhanced cell migration of both BxPC3 and BxPC3-SMAD4+, rendering the cells less sensitive to the other inflammatory stimuli. In conclusion, SMAD4 HD is associated with the constitutive activation of the ERK and Wnt/\u3b2-catenin signalling pathways, and favors the EGF-induced activation of multiple signalling pathways critical to cancer proliferation and invasion. TGF\u3b21 and S100A8/A9 mainly inhibit NF-\u3baB and PI3K/AKT pathways and, when combined, sinergize with EGF in enhancing anti-apoptotic p-BAD in a SMAD4-dependent manner

Proteomic study identifies glycolytic and inflammation pathways involved in recurrent otitis media

Recurrent acute otitis media (RAOM) in children is clinically defined as the occurrence of at least three episodes of acute otitis media over a course of 6 months. A further common pathological condition of interest in the context of pediatric otolaryngology is adenotonsillar hypertrophy (ATH), a common cause of obstructive sleep apnea syndrome. Aimed at unraveling the differential modulation of proteins in the two pathologies and at understanding the possible pathways involved in their onset, we analyzed the proteomic profile of the adenoids from 14 RAOM and ATH patients by using two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). The 2-DE coupled with MS allowed us to identify 23 spots with significant (p-value < 0.05) changes in protein amount, recognizing proteins involved in neutrophil degranulation and glycolysis pathways.This research was funded by I.R.C.C.S. “B. G.”, grant number RC 02/20 and RC 15/17

Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the FIL MCL0208 trial

In the FIL MCL0208 phase III trial, lenalidomide maintenance (LEN) after transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell surface receptors might predict drug efficacy. Genotypes were obtained by real-time polymerase chain reaction (RT-PCR) in peripheral blood (PB) germ line DNA. Polymorphisms of either ABCB1 or VEGF were found in 69% and 79% of 278 patients and predicted favorable PFS vs homozygous wild type (WT) in the LEN arm: 3-year PFS 85% vs 70% (p < 0.05) and 85% vs 60% (p < 0.01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (OS, 76%): in fact, in these patients LEN did not improve PFS vs OBS (3-year PFS 44% vs 60%, p = 0.62). Moreover, CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, while ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL. This trial is registered at eudract.ema.europa.eu as 2009-012807-25

Living on the Edge: Assessing the Extinction Risk of Critically Endangered Bonelli’s Eagle in Italy

Background: The population of Bonelli’s eagle (Aquila fasciata) has declined drastically throughout its European range due to habitat degradation and unnatural elevated mortality. There are less than 1500 breeding pairs accounted for in Europe, and the species is currently catalogued as Critically Endangered in Italy, where the 22 territories of Sicily, represent nearly 95% of the entire Italian population. However, despite national and European conservation concerns, the species currently lacks a specific conservation plan, and no previous attempts to estimate the risk of extinction have been made. Methodology/Principal Findings: We incorporated the most updated demographic information available to assess the extinction risk of endangered Bonelli’s eagle in Italy through a Population Viability Analysis. Using perturbation analyses (sensitivity and elasticity), and a combination of demographic data obtained from an assortment of independent methods, we evaluated which demographic parameters have more influence on the population’s fate. We also simulated different scenarios to explore the effects of possible management actions. Our results showed that under the current conditions, Bonelli’s eagle is expected to become extinct in Italy in less than 50 years. Stand-alone juvenile mortality was the most critical demographic parameter with the strongest influence on population persistence with respect to other demographic parameters. Measures aimed at either decreasing juvenile mortality, adult mortality or decreasing both juvenile and adult mortality resulted in equivalent net positive effects on population persistence (population growth rate l.1). In contrast, changes aimed at increasing breeding success had limited positive effects on demographic trends. Conclusions/Significance: Our PVA provides essential information to direct the decision-making process and exposes gaps in our previous knowledge. To ensure the long-term persistence of the species in Italy, measures are urgently needed to decrease both adult mortality due to poaching and juvenile mortality due to nest plundering, the top ranking mortality causes.PLL is supported by a “Juan de la Cierva” postdoctoral grant of the Spanish Ministry of Economy and Competitiveness (reference JCI-2011–09588)

Life cycle assessment of natural building materials: the role of carbonation, mixture components and transport in the environmental impacts of hempcrete blocks

Hempcrete is a natural building material that, in recent years, has known an increased popularity in a number of European countries. Hempcrete-based construction materials are used in non-bearing walls, as finishing plasters and floor/roof insulators. In the present work, the environmental performances of a non-load-bearing wall made of hempcrete blocks were assessed via Life Cycle Assessment (LCA). The analysis encompassed the whole life cycle but the end of life, due to the lack of reliable data for this stage. The production phase of the raw materials was identified as the main source of environmental impacts, but the transport distance of raw materials, as well as the amount and composition of the binder mixture, can considerably affect the results. An experimental assessment (via X-ray Powder Diffraction analysis) of the carbonation process taking place within the binder during the use phase of the wall showed that the carbonation rate may be smaller than assumed in previous works: after 240\uc2\ua0d, only the outermost layers of the blocks showed significant levels of carbonation, while the innermost layers experienced only a negligible increase in the amount of carbonates. Nevertheless, the overall emission balance is very favourable: thanks to biogenic CO2 uptake during hemp growth and to CO2 uptake by carbonation, hempcrete blocks have a negative carbon footprint and act therefore as effective carbon sinks

Efficacy and safety of ribosome-component immune modulator for preventing recurrent respiratory infections in socialized children

Attending day care is associated with recurrent respiratory infections (RRIs) and asthma. Ribosomal immunotherapy may confer protection against RRIs in children. This study was designed to assess the efficacy of a ribosome-component immune modulator (RCIM) as preventive treatment of respiratory infections in socialized children aged 645 years, with or without a history of frequent RRI. In a multicenter, Italian, randomized, double-blind, placebo-controlled, parallel-group study, 164 socialized day care center children (mean age, 3.8 \ub1 1.1 years) were treated with RCIM or placebo for 6 months and followed-up for additional 6 months. Outcomes are presented for the intent-to-treat population. In socialized children with five or less RRIs (n = 95; 49 RCIM and 46 placebo, group A) the duration of the infectious episodes was significantly shorter with RCIM than with placebo (6 months, 3.7 \ub1 2.1 versus 4.5 \ub1 1.9 days, p = 0.040; 12 months, 3.6 \ub1 2.0 versus 4.7 \ub1 2.5 days, p = 0.015). The proportion of patients reporting no respiratory infectious episodes with RCIM at 6 and 12 months was also significantly larger in group A (20.4% versus 4.4% placebo; p = 0.028). No such differences were found in children with more than five RRIs in the preceding year (n = 63; 32 RCIM and 31 placebo, group B). In all children, general well-being improved significantly more under RCIM than under placebo (11.6 \ub1 1.8% versus 10.2 \ub1 1.8%; p = 0.002). No statistically significant between-treatment differences were observed for other end points. Both treatments were similarly well tolerated. Six-month treatment with RCIM effectively prevented the 12-month risk of RRIs in children <5 years old and with five or less RRIs in the preceding year