miRNA Expression May Have Implications for Immunotherapy in PDGFRA Mutant GISTs

Gastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5–7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is correlated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different biological behavior of this GIST subset.     

Managing evolutionary paths in Sales and Operations Planning: key dimensions and sequences of implementation

Sales and Operations Planning (S&OP) is a key process that improves integration and communication between business functions and aligns the plans of a company into one integrated set of plans. This article focuses on the so-called S&OP ‘maturity models’, which describe the successive stages in the advancement of S&OP process according to a precise set of dimensions. These models are specifically thought to plan the transitions towards advanced stages, rather than to provide guidance on how to execute them. This paper aims to address this research gap by investigating how the dimensions evolve and interact during the execution of the transition between two subsequent stages. Three case studies of S&OP transitions with different starting and destination maturity stages have been compared. The findings demonstrate that the degree of seriality vs. parallelism among actions on different S&OP dimensions during the transition depends on the evolution stage of S&OP process. The study sheds light on the dynamics among the dimensions during the different transitions and warns managers not to underestimate the criticality of the people and organisation dimension, whose importance grows as the maturity level increases.     

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system. At present, there is no definitive cure, and the few available disease-modifying options display either poor efficacy or life-threatening side effects. There is clear evidence that relapsing-remitting clinical attacks in MS are driven by inflammatory demyelination and that the subsequent disease steps, being irresponsive to immunotherapy, result from neurodegeneration. The endocannabinoid system (ECS) stands halfway between three key pathomechanisms underlying MS, namely inflammation, neurodegeneration and oxidative stress, thus representing a kingpin for the identification of novel therapeutic targets in MS. This review summarizes the current state of the art in the field of endocannabinoid metabolism modulators and their in vivo effects on relevant animal models. We also highlight key molecular underpinnings of their therapeutic efficacy as well as the potential to turn them into promising clinical candidates.     

Outcomes of Lower Extremity Endovascular Revascularization: Potential Predictors and Prevention Strategies

Peripheral artery disease (PAD) is a manifestation of atherosclerosis, which may affect arteries of the lower extremities. The most dangerous PAD complication is chronic limb-threatening ischemia (CLTI). Without revascularization, CLTI often causes limb loss. However, neither open surgical revascularization nor endovascular treatment (EVT) ensure long-term success and freedom from restenosis and revascularization failure. In recent years, EVT has gained growing acceptance among all vascular specialties, becoming the primary approach of revascularization in patients with CLTI. In clinical practice, different clinical outcomes after EVT in patients with similar comorbidities undergoing the same procedure (in terms of revascularization technique and localization of the disease) cause unsolved issues that need to be addressed. Nowadays, risk management of revascularization failure is one of the major challenges in the vascular field. The aim of this literature review is to identify potential predictors for lower extremity endovascular revascularization outcomes and possible prevention strategies.     

Iron Availability in Tissue Microenvironment: The Key Role of Ferroportin

Body iron levels are regulated by hepcidin, a liver-derived peptide that exerts its function by controlling the presence of ferroportin (FPN), the sole cellular iron exporter, on the cell surface. Hepcidin binding leads to FPN internalization and degradation, thereby inhibiting iron release, in particular from iron-absorbing duodenal cells and macrophages involved in iron recycling. Disruption in this regulatory mechanism results in a variety of disorders associated with iron-deficiency or overload. In recent years, increasing evidence has emerged to indicate that, in addition to its role in systemic iron metabolism, FPN may play an important function in local iron control, such that its dysregulation may lead to tissue damage despite unaltered systemic iron homeostasis. In this review, we focus on recent discoveries to discuss the role of FPN-mediated iron export in the microenvironment under both physiological and pathological conditions.     

Extensive Placental Methylation Profiling in Normal Pregnancies

The placental methylation pattern is crucial for the regulation of genes involved in trophoblast invasion and placental development, both key events for fetal growth. We investigated LINE-1 methylation and methylome profiling using a methylation EPIC array and the targeted methylation sequencing of 154 normal, full-term pregnancies, stratified by birth weight percentiles. LINE-1 methylation showed evidence of a more pronounced hypomethylation in small neonates compared with normal and large for gestational age. Genome-wide methylation, performed in two subsets of pregnancies, showed very similar methylation profiles among cord blood samples while placentae from different pregnancies appeared very variable. A unique methylation profile emerged in each placenta, which could represent the sum of adjustments that the placenta made during the pregnancy to preserve the epigenetic homeostasis of the fetus. Investigations into the 1000 most variable sites between cord blood and the placenta showed that promoters and gene bodies that are hypermethylated in the placenta are associated with blood-specific functions, whereas those that are hypomethylated belong mainly to pathways involved in cancer. These features support the functional analogies between a placenta and cancer. Our results, which provide a comprehensive analysis of DNA methylation profiling in the human placenta, suggest that its peculiar dynamicity can be relevant for understanding placental plasticity in response to the environment.     

Evaluation of the effects of silver nanoparticles on Danio rerio cornea: Morphological and ultrastructural analysis

Although in recent years there has been intensification in the use of nanoparticles (NPs) for the production of many commercial products, few studies have been carried out to assess the risks associated with its use. Among the most used NPs, silver nanoparticles (AgNPs) have a preponderant position as they have various applications. In this study, 40 adult zebrafish were exposed to increasing concentrations of AgNPs (8, 45, and 70 μg/L) for 30 days to evaluate the effects on eyes after chronic exposure to AgNPs with an average diameter of 50 nm. From the morphological and ultrastructural analysis performed, no alteration or lesions of the corneal epithelium were detected.     

Destructuration of typical Sicilian calcarenites

The paper discusses some interesting features of Sicilian fine grain calcarenites. Uniaxial, triaxial, oedometer and isotropic compression tests were undertaken on intact specimens of two types of calcarenite in order to investigate their mechanical characteristics. It was found that the strength and deformability is significantly influenced by the structure (fabric and bonding) and by the destructuration processes. A better understanding of fracture development behavior is gained through a combination of acoustic emission and photographic monitoring on non-homogeneous samples with natural pre-existing heterogeneities due to cementation or to density. The results show that the destructuration and fracture propagation, as well as the structural strength, are highly dependent on the position and distribution of heterogeneities in the sample. With the Marsala calcarenite, the critical state was not reached, even with large strains, while with the Palermo calcarenite, the critical state was reached for lower strain values and the material demonstrated the yielding behavior typical of brittle rocks.