•Axl/Gas6 are overexpressed in several cancer types.•Axl/Gas6 regulate the epithelial-mesenchymal transition and cancer metastatic spread.•Axl/Gas6 are involved in oligodendrocytes survival and ...multiple sclerosis.•Axl/Gas6 favor Zika virus infection acting as cell entry door.•Novel molecules interacting with or modulating Axl/Gas6 are needed for clinical use.
Axl receptor tyrosine kinase (RTK) and its ligand, growth arrest-specific protein 6 (Gas6), are involved in several biological functions and participate in the development and progression of a range of malignancies and autoimmune disorders. In this review, we present this molecular system from a drug discovery perspective, highlighting its therapeutic implications and challenges that need to be addressed. We provide an update on Axl/Gas6 axis biology, exploring its role in fields ranging from angiogenesis, cancer development and metastasis, immune response and inflammation to viral infection. Finally, we summarize the molecules that have been developed to date to target the Axl/Gas6 molecular system for therapeutic and diagnostic applications.
We provide an overview of Axl/Gas6 biology and pathology for insights for the development of novel drugs.
Despite neonatal lung ultrasound (LU) being diffused worldwide, its introduction in limited-resource areas has not been formally investigated. We conceived a project to introduce it in a level 3 NICU ...of a developing country and verify if, after a short protocolized training, clinicians may efficaciously use LU. Inter-rater agreement between ultrasound trainees and trainers was analyzed within both the local test and the diffusion phases of the project. High inter-rater agreements were found between expert trainers and the two neonatologists who were trained in a skilled European center (Cohen’s Kappa, 0.951; 95%CI, 0.882–0.999), as well as between the two and the second round of locally trained colleagues (Cohen’s Kappa, 0.896; 95%CI, 0.797–0.996). Moreover, a high agreement was found between the clinical respiratory diagnosis (used as the “gold standard”) and the LU diagnosis given by the first two trainees (intraclass correlation, 0.992; 95%CI, 0.987–0.996) and the locally trained physicians (intraclass correlation, 0.97; 95%CI, 0.95–0.98). A final survey demonstrated that the project was perceived as efficacious and that LU was going to be integrated into routine clinical practice.
Conclusions
: А short LU training provided sufficient proficiency and allowed the LU introduction in clinical practice in the neonatal intensive care unit in a developing country.
What is Known:
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Lung ultrasound is a promising technique for evaluating neonatal respiratory distress at least in high-income countries. Previous studies revealed high specificity and sensitivity in diagnosing specific neonatal disorders.
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An important barrier to the more extensive use of lung ultrasound in neonatal critical care is a lack of efficient and suitable training solutions.
What is New:
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Descriptive LU performed by neonatologist in a developing country after a short formal training is feasible with good quality.
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A short formal LU training program provided good proficiency and allowed a correct descriptive diagnosis in a neonatal unit in a developing country.
•Several lines of preclinical evidence link the AXL/GAS6 protein system to colorectal cancer.•Axl overexpression is a negative prognostic factor in colorectal cancer.•Drugs inhibiting the Axl ...receptor are under clinical evaluation for colorectal cancer.•Molecules targeting the Axl receptor could expand the tools to combat colorectal cancer.
AXL receptor tyrosine kinase (AXL) is a receptor tyrosine kinase whose aberrant expression has recently been associated with colorectal cancer (CRC), contributing to tumor growth, epithelial–mesenchymal transition (EMT), increased invasiveness, metastatic spreading, and the development of drug resistance. In this review we summarize preclinical data, the majority of which are limited to recent years, convincingly linking the AXL receptor to CRC. These findings support the value of targeting AXL with molecules in drug discovery, offering novel and advanced therapeutic or diagnostic tools for CRC management.
► We evaluate the performance of a BFS adapted for flood prediction in a small basin. ► Hydrologic uncertainty is crucial for the predictive distribution of river discharge. ► Four hypotheses, ...resulting from the BFS properties, were examined. ► The results emphasize the importance of using different diagnostic approaches to analyze the forecast quality.
The paper evaluates, for a number of flood events, the performance of a Bayesian Forecasting System (BFS), with the aim of evaluating total uncertainty in real-time flood forecasting. The predictive uncertainty of future streamflow is estimated through the Bayesian integration of two separate processors. The former evaluates the propagation of input uncertainty on simulated river discharge, the latter computes the hydrological uncertainty of actual river discharge associated with all other possible sources of error.
A stochastic model and a distributed rainfall–runoff model were assumed, respectively, for rainfall and hydrological response simulations. A case study was carried out for a small basin in the Calabria region (southern Italy).
The performance assessment of the BFS was performed with adequate verification tools suited for probabilistic forecasts of continuous variables such as streamflow. Graphical tools and scalar metrics were used to evaluate several attributes of the forecast quality of the entire time-varying predictive distributions: calibration, sharpness, accuracy, and continuous ranked probability score (CRPS).
Besides the overall system, which incorporates both sources of uncertainty, other hypotheses resulting from the BFS properties were examined, corresponding to (i) a perfect hydrological model; (ii) a non-informative rainfall forecast for predicting streamflow; and (iii) a perfect input forecast.
The results emphasize the importance of using different diagnostic approaches to perform comprehensive analyses of predictive distributions, to arrive at a multifaceted view of the attributes of the prediction. For the case study, the selected criteria revealed the interaction of the different sources of error, in particular the crucial role of the hydrological uncertainty processor when compensating, at the cost of wider forecast intervals, for the unreliable and biased predictive distribution resulting from the Precipitation Uncertainty Processor.
Folding stability is a crucial feature of protein evolution and is essential for protein functions. Thus, the comprehension of protein folding mechanisms represents an important complement to protein ...structure and function, crucial to determine the structural basis of protein misfolding. In this context, thermal unfolding studies represent a useful tool to get a molecular description of the conformational transitions governing the folding/unfolding equilibrium of a given protein. Here, we report the thermal folding/unfolding pathway of VEGFR1D2, a member of the immunoglobulin superfamily by means of a high‐resolution thermodynamic approach that combines differential scanning calorimetry with atomic‐level unfolding monitored by NMR. We show how VEGFR1D2 folding is driven by an oxidatively induced disulfide pairing: the key event in the achievement of its functional structure is the formation of a small hydrophobic core that surrounds a disulfide bridge. Such a ‘folding nucleus’ induces the cooperative transition to the properly folded conformation supporting the hypothesis that a disulfide bond can act as a folding nucleus that eases the folding process.
A high‐resolution thermodynamic approach that combines differential scanning calorimetry with atomic‐level unfolding monitored by Nuclear Magnetic Resonance describes the thermal folding/unfolding pathway of VEGFR1D2, a member of the immunoglobulin superfamily. Such characterization unveils the existence of a small ‘folding nucleus’ surrounding the disulfide bridge that induces the cooperative transition from the unfolded VEGFR1D2 structure to the properly folded functional conformation.
Copy number variants (CNVs) have a major role in the etiology of autism spectrum disorders (ASD), and several of these have reached statistical significance in case-control analyses. Nevertheless, ...current ASD cohorts are not large enough to detect very rare CNVs that may be causative or contributory (that is, risk alleles). Here, we use a tiered approach, in which clinically significant CNVs are first identified in large clinical cohorts of neurodevelopmental disorders (including but not specific to ASD), after which these CNVs are then systematically identified within well-characterized ASD cohorts. We focused our initial analysis on 48 recurrent CNVs (segmental duplication-mediated 'hotspots') from 24 loci in 31 516 published clinical cases with neurodevelopmental disorders and 13 696 published controls, which yielded a total of 19 deletion CNVs and 11 duplication CNVs that reached statistical significance. We then investigated the overlap of these 30 CNVs in a combined sample of 3955 well-characterized ASD cases from three published studies. We identified 73 deleterious recurrent CNVs, including 36 deletions from 11 loci and 37 duplications from seven loci, for a frequency of 1 in 54; had we considered the ASD cohorts alone, only 58 CNVs from eight loci (24 deletions from three loci and 34 duplications from five loci) would have reached statistical significance. In conclusion, until there are sufficiently large ASD research cohorts with enough power to detect very rare causative or contributory CNVs, data from larger clinical cohorts can be used to infer the likely clinical significance of CNVs in ASD.
Therapeutic hypothermia (TH) enhances pulmonary surfactant performance in vivo by molecular mechanisms still unknown. Here, the interfacial structure and the composition of lung surfactant films have ...been analysed in vitro under TH as well as the molecular basis of its improved performance both under physiological and inhibitory conditions. The biophysical activity of a purified porcine surfactant was tested under slow and breathing-like dynamics by constrained drop surfactometry (CDS) and in the captive bubble surfactometer (CBS) at both 33 and 37 °C. Additionally, the temperature-dependent surfactant activity was also analysed upon inhibition by plasma and subsequent restoration by further surfactant supplementation. Interfacial performance was correlated with lateral structure and lipid composition of films made of native surfactant. Lipid/protein mixtures designed as models to mimic different surfactant contexts were also studied. The capability of surfactant to drastically reduce surface tension was enhanced at 33 °C. Larger DPPC-enriched domains and lower percentages of less active lipids were detected in surfactant films exposed to TH-like conditions. Surfactant resistance to plasma inhibition was boosted and restoration therapies were more effective at 33 °C. This may explain the improved respiratory outcomes observed in cooled patients with acute respiratory distress syndrome and opens new opportunities in the treatment of acute lung injury.
Angiogenesis is a biological process finely tuned by a plethora of pro- and anti-angiogenic molecules, among which vascular endothelial growth factors (VEGFs). Their biological activity is expressed ...through the interaction with three cognate receptor tyrosine kinases, VEGFR1, 2, and 3. VEGFR2 is the primary regulator of angiogenesis. Ligand-induced VEGFR2 dimerization and activation depend on direct ligand binding to extracellular domains 2 and 3 of receptor and in the establishment of interactions between proximal membrane domains. VEGFR2 domain 7 has been shown to play a crucial role in receptor dimerization and regulation, therefore, representing a convenient target for the allosteric modulation of VEGFR2 activity. The ability to prepare a functional VEGFR2D7 domain represents the starting point to the development of novel VEGFR2 binders acting as allosteric inhibitors of receptor activity. Here, we describe a robust and efficient procedure for the preparation in
E. coli
of the VEGFR2 domain 7. The protein was obtained with a good yield and was properly folded. It was investigated in a biochemical and structural study, providing information on its conformational arrangement and in solution properties.
To investigate the accuracy of electrical cardiometry (EC) to measure stroke volume (SV) and cardiac output (CO) and to provide gestational age (GA) and birth weight (BW)-based reference data for SV ...and CO in hemodynamically stable preterm neonates.
Prospective observational blinded study. Paired measurements of SV and CO on stable preterm infants without any hemodynamic compromise were carried out using EC (SVEC) and echocardiography (SVECHO).
Seventy-nine preterm neonates (mean GA: 31±3.2 weeks) were enrolled. A good correlation was found for SV (r=0.743; P<0.0001) and CO (r=0.7; P<0.0001) measured by EC and echocardiography. These correlations remained significant after adjusting for GA, patent ductus arteriosus and type of respiratory support (SV: St.β=0.48, P<0.0001 and CO: St.β=0.69, P<0.0001). Mean biases (and variabilities) were -1.1 (from 0.7 to -2.9) ml and -0.21 (from 0.15 to -0.55) l min(-1) for SV and CO, respectively. Local regression shows a tendency for EC to overestimate SV and CO especially at higher values (at about >2 ml and >0.4 l min(-1), respectively). Coefficient of variation of SV was 48.9% and 52%, for EC and echocardiography. SV and CO rose with increasing GA and BW following an exponential equation (R(2)>0.8).
Measuring SV and CO with EC in hemodynamically stable preterm infants shows good correlation and variability similar to that of echocardiography. A trend to overestimation exists at highest values, but it is unlikely to be clinically significant. Reference GA and BW-based nomograms for SV and CO are provided.
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