Association of FGFR1 with ER-alpha maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER+ breast cancer

In a cohort of patients with ER+ breast cancer, tumors with FGFR1 amplification retained high proliferation upon estrogen deprivation with the aromatase inhibitor letrozole. Estrogen deprivation increased total and nuclear FGFR1 and FGF ligands in ER+/FGFR1-amplified primary tumors and breast cancer cells. In estrogen-free conditions, FGFR1 associated with ER-alpha in tumor cell nuclei and regulated the transcription of ER-dependent genes. This interaction and transcriptional output were inducible by FGF ligands and blocked by a kinase-dead FGFR1 mutant or FGFR kinase inhibitors. ChIP-seq of FGFR1 amplified cells treated with FGF3 showed binding of FGFR1 and ERα to DNA. Treatment with the ER downregulator fulvestrant and/or the FGFR inhibitor lucitanib reduced binding of ERα or FGFR1 to DNA. RNA-seq data from FGFR1-amplified patients’ tumors treated with letrozole showed enrichment of estrogen response and E2F target genes. Finally, growth of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts was more potently inhibited by fulvestrant and lucitanib combined than each drug alone, suggesting a causal association of aberrant FGFR signaling with endocrine resistance. These data suggest the ER-alpha pathway is still active in estrogen-deprived ER+/FGFR1-amplified breast cancers and, therefore, these tumors should be considered for treatment with a combination of ER and FGFR antagonists

Specification of skeletal muscle differentiation by repressor element-1 silencing transcription factor (REST)-regulated Kv7.4 potassium channels

Changes in the expression of potassium (K(+)) channels is a pivotal event during skeletal muscle differentiation. In mouse C(2)C(12) cells, similarly to human skeletal muscle cells, myotube formation increased the expression of K(v)7.1, K(v)7.3, and K(v)7.4, the last showing the highest degree of regulation. In C(2)C(12) cells, K(v)7.4 silencing by RNA interference reduced the expression levels of differentiation markers (myogenin, myosin heavy chain, troponinT-1, and Pax3) and impaired myotube formation and multinucleation. In K(v)7.4-silenced cells, the differentiation-promoting effect of the K(v)7 activator N-(2-amino-4-(4-fluorobenzylamino)-phenyl)-carbamic acid ethyl ester (retigabine) was abrogated. Expression levels for the repressor element-1 silencing transcription factor (REST) declined during myotube formation. Transcript levels for K(v)7.4, as well as for myogenin, troponinT-1, and Pax3, were reduced by REST overexpression and enhanced upon REST suppression by RNA interference. Four regions containing potential REST-binding sites in the 5′ untranslated region and in the first intron of the K(v)7.4 gene were identified by bioinformatic analysis. Chromatin immunoprecipitation assays showed that REST binds to these regions, exhibiting a higher efficiency in myoblasts than in myotubes. These data suggest that K(v)7.4 plays a permissive role in skeletal muscle differentiation and highlight REST as a crucial transcriptional regulator for this K(+) channel subunit

Assessment of the design criteria for concentric V-braced steel structures according to Italian and European codes

The critical review of design methodologies provided by the NTC2008, in agreement with the European seismic code (Eurocode 8) for steel Concentrically Braced Frames with chevron (or inverted V) diagonals (CBF-V), carried out by deepening the seismic behaviour of such typical steel seismic resistant structures, aims to provide more efficient design criteria able to ensure adequate safety levels under seism. As reference case studies, common structural configurations of CBF-V are designed according to the NTC2008 provisions. Each case study is designed through both the Linear Static (LS) and Dynamic (LD) analysis. For braces either Circular Hollow Sections (CHS) or HE profiles are used. General critical issues have been evidenced in the design process. The seismic performance of investigated structures is evaluated by non-linear static analyses, in order to appraise the most relevant behavioural issues, like the behaviour factor, the failure modes and the effectiveness of the capacity design criteria. A discussion on the obtained results has allowed to point out the pros and cons of the current design approach

Experimental Investigations on Bending Collapse Modes of Innovative Sandwich Panels with Metallic Foam Core

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Role of Endoscopy in Tracheo-esophageal Prosthesis Phonation. Technical and Psychological Aspects. Our Institutional Experience

In our study, we have analyzed the use of flexible video endoscopy in patients undergoing total laryngectomy and candidates for the placement of a voice prosthesis, with the creation of a tracheo-esophageal fistula in which the prosthesis is positioned, which acts as a valve one-way, which allows the passage of air from the trachea to the oesophagus and prevents the passage of liquids in the opposite direction, allowing the pulmonary air to vibrate a segment of the cervical oesophagus. The use of flexible video endoscopy for the positioning of the prosthesis can be both primary and secondary to the intervention of total laryngectomy. Endoscopy has also been used in the ontological follow-up for the assessment of the hypo pharyngeal-oesophageal-gastric district in the search for relapses or secondary tumors, which may develop in this district in more than 10% of patients with pathological neoplasia. Higher aero-digestiv

Resveratrol via sirtuin-1 downregulates RE1-silencing transcription factor (REST) expression preventing PCB-95-induced neuronal cell death

Resveratrol (3,5,4'-trihydroxystilbene) (RSV), a polyphenol widely present in plants, exerts a neuroprotective function in several neurological conditions; it is an activator of class III histone deacetylase sirtuin1 (SIRT1), a crucial regulator in the pathophysiology of neurodegenerative diseases. By contrast, the RE1-silencing transcription factor (REST) is involved in the neurotoxic effects following exposure to polychlorinated biphenyl (PCB) mixture A1254. The present study investigated the effects of RSV-induced activation of SIRT1 on REST expression in SH-SY5Y cells. Further, we investigated the possible relationship between the non-dioxin-like (NDL) PCB-95 and REST through SIRT1 to regulate neuronal death in rat cortical neurons. Our results revealed that RSV significantly decreased REST gene and protein levels in a dose- and time-dependent manner. Interestingly, overexpression of SIRT1 reduced REST expression, whereas EX-527, an inhibitor of SIRT1, increased REST expression and blocked RSV-induced REST downregulation. These results suggest that RSV downregulates REST through SIRT1. In addition, RSV enhanced activator protein 1 (AP-1) transcription factor c-Jun expression and its binding to the REST promoter gene. Indeed, c-Jun knockdown reverted RSV-induced REST downregulation. Intriguingly, in SH-SY5Y cells and rat cortical neurons the NDL PCB-95 induced necrotic cell death in a concentration-dependent manner by increasing REST mRNA and protein expression. In addition, SIRT1 knockdown blocked RSV-induced neuroprotection in rat cortical neurons treated with PCB-95. Collectively, these results indicate that RSV via SIRT1 activates c-Jun, thereby reducing REST expression in SH-SY5Y cells under physiological conditions and blocks PCB-95-induced neuronal cell death by activating the same SIRT1/c-Jun/REST pathway

BioEnterics Intragastric Balloon (BIB) versus Spatz Adjustable BalloonSystem (ABS): Our experience in the elderly

The BioEnterics Intragastric Balloon (BIB) and the Spatz Adjustable Balloon System (ABS) are in fact recommended for weight reduction as a bridge to bariatric surgery. We retrospected studied patients with body mass index (BMI) and age ranges of 37e46 and 70e80 years, respectively, who had undergone BIB from January 2010 to July 2012 and prospected studied patients who had undergone Spatz balloon from July 2012 to August 2014. The aim of this study is to compare BIB and Spatz in terms of weight loss, complications, and maintenance of weight after removal. For both procedures, the median weight loss was 20 ± 3 kg, median BMI at the end of the therapy was 32 ± 2, and no severe complication occurred

resveratrol treatment reduces the vulnerability of sh sy5y cells and cortical neurons overexpressing sod1 g93a to thimerosal toxicity through sirt1 dream pdyn pathway

Abstract In humans, mutation of glycine 93 to alanine of Cu++/Zn++ superoxide dismutase type-1 (SOD1-G93 A) has been associated to some familial cases of Amyotrophic Lateral Sclerosis (ALS). Several evidence proposed the involvement of environmental pollutants that like mercury could accelerate ALS symptoms. SH-SY5Y cells stably transfected with SOD1 and G93 A mutant of SOD1 constructs were exposed to non-toxic concentrations (0.01 μM) of ethylmercury thiosalicylate (thimerosal) for 24 h. Interestingly, we found that thimerosal, in SOD1-G93 A cells, but not in SOD1 cells, reduced cell survival. Furthermore, thimerosal-induced cell death occurred in a concentration dependent-manner and was prevented by the Sirtuin 1 (SIRT1) activator Resveratrol (RSV). Moreover, thimerosal decreased the protein expression of transcription factor Downstream Regulatory Element Antagonist Modulator (DREAM), but not DREAM gene. Interestingly, DREAM reduction was blocked by co-treatment with RSV, suggesting the participation of SIRT1 in determining this effect. Immunoprecipitation experiments in SOD1-G93 A cells exposed to thimerosal demonstrated that RSV increased DREAM deacetylation and reduced its polyubiquitination. In addition, RSV counteracted thimerosal-enhanced prodynorphin (PDYN) mRNA, a DREAM target gene. Furthermore, cortical neurons transiently transfected with SOD1-G93 A construct and exposed to thimerosal (0.5 μM/24 h) showed a reduction of DREAM and an up-regulation of the prodynorphin gene. Importantly, both the treatment with RSV or the transfection of siRNA against prodynorphin significantly reduced thimerosal-induced neurotoxicity, while DREAM knocking-down potentiated thimerosal-reduced cell survival. These results demonstrate the particular vulnerability of SOD1-G93 A neuronal cells to thimerosal and that RSV via SIRT1 counteracts the neurodetrimental effect of this toxicant by preventing DREAM reduction and prodynorphin up-regulation

Morpho-Physiological and Biochemical Responses of Hydroponically Grown Basil Cultivars to Salt Stress

Depending on duration and magnitude, abiotic stresses interfere with plant metabolic processes and may severely impact developmental and qualitative attributes. In this study, in addition to characterizing three different cultivars of basil (‘Anise’, ‘Cinnamon’, and ‘Lemon’) grown under hydroponics, we appraised the impact of NaCl salt stress (60 mM) on morphophysiological and nutraceutical properties of the basil crop. Salt stress significantly reduced fresh yield (51.54%, on average) and photosynthetic parameters (ACO2, E, and gs) in all cultivars by raising tissue concentrations of Na+ and Cl−. In addition to reducing the concentration of nitrate (77.21%), NaCl salt stress increased the concentrations of key bioactive molecules, notably carotenoids (lutein and β-carotene), phenolic acids, and flavonoid derivatives, thus resulting in a higher antioxidant activity of salt-treated basil plants compared to the untreated ones. Analysis by UHPLC revealed that cichoric acid was the most abundant polyphenolic compound in all basil cultivars, with the highest values recorded in ‘Cinnamon’