Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma

ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients—and classified by in silico tools as pathogenic, uncertain significance, or benign—using multiple assays evaluating ATM/pATM expression and/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum.     

Pharmacological and In Silico Analysis of Oat Avenanthramides as EGFR Inhibitors: Effects on EGF-Induced Lung Cancer Cell Growth and Migration

Avena sativa L. is a wholegrain cereal and an important edible crop. Oats possesses high nutritional and health promoting values and contains high levels of bioactive compounds, including a group of phenolic amides, named avenanthramides (Avns), exerting antioxidant, anti-inflammatory, and anticancer activities. Epidermal growth factor receptor (EGFR) represents one of the most known oncogenes and it is frequently up-regulated or mutated in human cancers. The oncogenic effects of EGFR include enhanced cell growth, angiogenesis, and metastasis, and down-regulation or inhibition of EGFR signaling has therapeutic benefit. Front-line EGFR tyrosine kinase inhibitor therapy is the standard therapy for patients with EGFR-mutated lung cancer. However, the clinical effects of EGFR inhibition may be lost after a few months of treatment due to the onset of resistance. Here, we showed the anticancer activity of Avns, focusing on EGFR activation and signaling pathway. Lung cancer cellular models have been used to evaluate the activity of Avns on tumor growth, migration, EMT, and anoikis induced by EGF. In addition, docking and molecular dynamics simulations showed that the Avns bind with high affinity to a region in the vicinity of αC-helix and the DGF motif of EGFR, jeopardizing the target biological function. Altogether, our results reveal a new pharmacological activity of Avns as EGFR tyrosine kinase inhibitors.     

On the control of non-linear processes: An IDA–PBC approach

A high performance non-linear controller that exploits the properties of port-Hamiltonian systems to precisely define the interconnections and energy dissipations of non-linear processes is presented for a large class of chemical processes. The controller is derived from classical interconnection and damping assignment–passivity based control theory but an additional degree of freedom is introduced in the controller design by the use of “non-exact matching” closed-loop storage functions. By a proper closed-loop interconnection assignment the proposed controller achieves total decoupling between outputs and since no inversion of the process dynamics is made in the design it is equally applicable to minimum phase and nonminimum phase system. The controller design methodology is presented and stability conditions are stated. As illustrative example the proposed method is used to design controllers for a multiple-input/multiple-output non-isothermal continued stirred tank reactor that exhibits nonminimum phase behavior.     

Real-time monitoring and characterization of flames by principal-component analysis

This work describes the characterization of combustion flames by using Principal-Component Analysis. Generalized Hebbian Learning is applied to extract the meaningful components from flame images; so that the operating conditions of the combustion process can be inferred by analyzing the lower dimensional PCA space. Experimental results demonstrate that GHL can effectively characterize the flame in terms of just a few components. It was found that the first principal component of a CCD image obtained from the blue channel is correlated with the air/gas flow rate. These results can be applied to real time monitoring and control of the combustion process.     

High-dose ethambutol: its role in intermittent chemotherapy. A six-year study

The outcome of 81 patients receiving supervised ambulatory treatment with twice-weekly isoniazid and ethambutol is reported. The patients were divided into 2 groups, one of which received its entire outpatient treatment with isoniazid and ethambutol, the other receiving isoniazid and ethambutol after initial treatment with isoniazid and streptomycin. In both groups, there was a 100 per cent favorable response at completion of therapy and no relapes detected among those patients followed after treatment. We compared our results with other studies of intermittent-supervised therapy and concluded that twice-weekly isoniazid and ethambutol given up to 18 months after an adequate phase of daily treatment is a highly effective and well-tolerated regimen.     

The MEK5/ERK5 Pathway in Health and Disease

The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.     

Control of silver-polymer aggregation mechanism by primary particle spatial correlations in dynamic fractal-like geometry

Silver nanocrystals have been prepared by reacting silver nitrate with ascorbic acid in aqueous solution containing a low concentration of a commercial polynaphthalene sulfonate polymer (Daxad 19). Various crystalline morphologies have been obtained simply by tuning the reaction temperature. We have investigated the nanoparticle formation mechanism at three different temperatures by in situ and time resolved small angle X-ray scattering measurements. By modeling the scattering intensity with interacting spherical particles in a fractal-like polymer-Ag matrix, we found signatures of nucleation, growth and assembly of primary particles of about 15-20 nm. We observed how the time evolution of both spatial correlations between primary particles and the dynamic fractal geometry of the polymer-Ag matrix could influence and determine both the aggregation mechanism and the morphology of forming nanostructures in solution.     

Hyperspectral transmittance imaging of the shell-free cooked clam Mulinia edulis for parasite detection

The clam Mulinia edulis is occasionally infected by the parasite Edotea magellanica. In this paper the normalized optical transmittance of the clam and its parasite have been disclosed for the first time using a hyperspectral imaging system. It has been identified that, in the spectral band of 600–950 nm, the normalized optical transmittance of clam’s mantle cavity changes in the presence or absence of the parasite. This relative change in the normalized optical transmittance has been used as an effective spectral feature for designing parasite detectors. As a proof of concept two detectors have been designed. The first detector, which relies on all the hyperspectral information, achieved a perfect detection accuracy in identifying parasite-infected clams. The second detector, which is based on a reduced number of hyperspectral bands, achieved an 85% detection accuracy. These results provide insights on the fundamental trade-off between detection accuracy and the amount of hyperspectral information for parasite detection in clams.     

The role of teat skin contamination in the epidemiology of Staphylococcus aureus intramammary infections

Knowledge of the epidemiological pattern and the potential sources of infections is important to control Staphylococcus aureus in dairy herds. This paper reports the results of a study applying both pulse field gel electrophoresis (PGFE) and the assessment of a selected number of virulence genes to investigate the role of teat skin on Staph. aureus transmission among cows and on the contamination of milk. Overall 61 isolates were considered, 23 from teat skin, 33 from milk samples and 5 from curd samples. Teat swabs were taken in five herds, but in only three of them could Staph. aureus be isolated. Curd was sampled in three herds, but Staph. aureus could be isolated in only two herds. The distribution of isolates among herds confirmed the presence of herd-specific Staph. aureus strain in most of the herds. The same pattern was observed in teat skin samples, in quarter milk samples, and in the curd samples. Our findings are consistent with other studies showing the role of teat skin as a potential reservoir. Moreover, Staph. aureus was isolated from teat skin of confirmed Staph. aureus-negative cows that were segregated from infected ones. Our findings also suggest that some strains have higher chances to survive on teat skin and therefore to increase the risk for contamination of milk and milk products due to the persistence of intramammary infections.     

Analysis of major proteins and fat fractions associated with mare's milk fat globules

Although several studies have aimed to identify mare's milk proteins, only the major whey proteins and some caseins have yet been characterized. Incomplete sequencing of the equine genome and the difficulty of recovering highly hydrophobic proteins mean that little is known to date about the proteins associated with milk fat globules, which have been shown to play an important role in newborns' defense mechanisms. The fat fraction, in particular the distribution of unsaturated fatty acids, has been more extensively studied, but complex lipids are only partially elucidated. This study reports a 2-DE approach combined with a powerful method for de novo protein sequencing, and quali-quantitative data on complex lipid composition determined by high performance TLC (HPTLC) and GC. The presence in mare's milk of long-chain highly unsaturated fatty acids, and the evidence of close similarity between equine and human milk fat globule membrane proteins, support the use of mare's milk for human nutrition.