miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer's disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications

Defibrotide impact on the acute GVHD disease incidence in pediatric hematopoietic stem cell transplant recipients

Despite advances in acute graft-versus-host disease (aGVHD) prophylaxis, current pharmacological approaches fail to prevent aGVHD. The protective effect of defibrotide on GVHD incidence and GVHD-free survival has not been sufficiently studied. 91 pediatric patients included in this retrospective study were divided into two groups based on defibrotide use. We compared the incidence of aGVHD and chronic GVHD-free survival between the defibrotide and control groups. The incidence and severity of aGVHD were significantly lower in patients who received defibrotide prophylactic administration than in the control group. This improvement was observed in the liver and intestinal aGVHD. No defibrotide prophylaxis benefit was observed in the prevention of chronic GVHD. The pro-inflammatory cytokine levels were significantly higher in the control group. Our findings suggest that prophylactic administration of defibrotide in pediatric patients significantly reduces the incidence and severity of aGVHD, with a modification of cytokine pattern, both strongly coherent with the protective drug's action. This evidence adds to pediatric retrospective studies and preclinical data suggesting a possible defibrotide role in this setting

serum soluble tumor necrosis factor related apoptosis inducing ligand levels in older subjects with dementia and mild cognitive impairment

Background: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been involved in both physiological and pathological conditions, including va

Venous compliance and clinical implications

Compliance is a characteristic of every deformable system. Compliance is very clear concept in physics and mechanics but in clinics, perhaps, is not the same. However, in veins compliance fits perfectly with the function of drainage of the venous system. Volumetric increase (dV) of the content is correlated with pressure increase (dP) inside the vein according to the equation C'= dV/dP. In humans 75% of the blood is located in the venous system, primarily because the molecular components of a vein media layer is significantly more compliant to that of arteries. This property is fundamental to understanding the change in blood volume in response to a change in posture. Measurements of venous compliance in clinical practice can be done by the means of ultrasound, as well as with the plethysmography. Ultrasound methods assimilate the cross sectional area to the volume of the vein, because it reflects the blood content. Changes in cross sectional area can be reliably measured in response to a change in posture, while pressure can be derived from the hydrostatic pressure changes. Venous compliance is of paramount importance also in pulsatile veins such as the inferior or superior vena cava and the jugular veins, where high resolution ultrasound may accurately derive the cross sectional area. Clinical implications of the mechanical properties of the venous wall are extensively discussed, including the need of dedicated venous stenting, which takes into account venous compliance as the main parameter of the venous function. In addition, venous compliance is the interpretative key for a better understanding of plethysmography curves, as well as of varicose veins and of their return to normal cross sectional area following ambulatory venous pressure reduction

Relationship between low levels of circulating TRAIL and atheromatosis progression in patients with chronic kidney disease.

Background: Chronic kidney disease (CKD) patients experience a high risk of cardiovascular disease (CV); however, the factors involved in CV-related morbidity and mortality in these patients have not been fully defined. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine, which exhibits pleiotropic activities on endothelial, vascular smooth muscle and inflammatory cells, with relevant effects on atheromatous plaque formation. On this basis, the present study aims to investigate the role of TRAIL in atheromatosis progression in CKD patients. Methods: Circulating TRAIL levels were measured in 378 CKD patients belonging to the Spanish National Observatory of Atherosclerosis in Nephrology (NEFRONA) study. All patients were free of previous CV events. Carotid and femoral B-mode ultrasound was performed to detect the presence of plaque at baseline and after 24 months of follow-up. Results: The lowest levels of TRAIL at baseline were significantly (p<0.05) associated with the appearance, after 24 months of follow-up, of at least two new atheromatous plaques in all territories and of one new plaque in the carotid artery, even after adjusting for CV risk factors. In addition, the patients with low levels of TRAIL at baseline were characterized by the presence of at least one hypoechoic plaque in the carotid artery. This association was significant (p<0.05) even after adjusting for CKD stage. Conclusions: Overall, the results of our study suggest TRAIL as an assertable independent prognostic biomarker for atheromatosis plaque formation in CKD patients. This observation further supports the potential role of TRAIL for the prevention/treatment of CV disease.The NEFRONA study was funded by a research grant from Abbvie and the Spanish government RETIC (RD16/0009/0011) and FISPI16/01354. MVA is the recipient of the Italian Ministry of Health grant No. GR-2013-0 2358192. SG is the recipient of the "Associazione Italiana per la Ricerca sul Cancro, AIRC" fellowship, No. 18055. Moreover, the authors would like to thank Fondazione Dott. Carlo Fornasini (Poggio Renatico, Ferrara, Italy). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Circulating TRAIL Shows a Significant Post-Partum Decline Associated to Stressful Conditions

Background: Since circulating levels of TNF-related apoptosis inducing ligand (TRAIL) may be important in the physiopathology of pregnancy, we tested the hypothesis that TRAIL levels change at delivery in response to stressful conditions. Methods/Principal Findings: We conducted a longitudinal study in a cohort of 73 women examined at week 12, week 16, delivery and in the corresponding cord blood (CB). Serum TRAIL was assessed in relationship with maternal characteristics and to biochemical parameters. TRAIL did not vary between 12 (67.6627.6 pg/ml, means6SD) and 16 (64.0616.2 pg/ml) weeks ’ gestation, while displaying a significant decline after partum (49.3626.4 pg/ml). Using a cut-off decline.20 pg/ml between week 12 and delivery, the subset of women with the higher decline of circulating TRAIL (41.7%) showed the following characteristics: i) nullipara, ii) higher age, iii) operational vaginal delivery or urgent CS, iv) did not receive analgesia during labor, v) induced labor. CB TRAIL was significantly higher (131.6652 pg/ml) with respect to the corresponding maternal TRAIL, and the variables significantly associated with the first quartile of CB TRAIL (,90 pg/ml) were higher prepregnancy BMI, induction of labor and fetal distress. With respect to the biochemical parameters, maternal TRAIL at delivery showed an inverse correlation with C-reactive protein (CRP), total cortisol, glycemia and insulin at bivariate analysis, but only with CRP at multivariate analysis

Mevalonate Kinase Deficiency and Squalene Synthase Inhibitor (TAK-475): The Balance to Extinguish the Inflammation

: Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do not act specifically on neural inflammation. According to the new emerging pharmacology trends, the repositioning of drugs from the indication for which they were originally intended to another one can make mechanistic-based medications easily available to treat rare diseases. According to this perspective, the squalene synthase inhibitor Lapaquistat (TAK-475), originally developed as a cholesterol-lowering drug, might find a new indication in MKD, by modulating the mevalonate cholesterol pathway, increasing the availability of anti-inflammatory isoprenoid intermediates. Using an in vitro model for MKD, we mimicked the blockade of the cholesterol pathway and evaluated the potential anti-inflammatory effect of Lapaquistat. The results obtained showed anti-inflammatory effects of Lapaquistat in association with a low blockade of the metabolic pathway, while this effect did not remain with a tighter blockade. On these bases, Lapaquistat could be configured as an effective treatment for MKD's mild forms, in which the residual enzymatic activity is only reduced and not almost completely absent as in the severe forms

Role of vitamin D in the pathogenesis of atheromatosis

Background and Aims Cardiovascular disease is the main cause of death worldwide, but the collective efforts to prevent this pathological condition are directed exclusively to individuals at higher risk due to hypercholesterolemia, hypertension, obesity, diabetes. Recently, vitamin D deficiency was identified as a risk factor for cardiovascular disease in healthy people, as it predisposes to different vascular dysfunctions that can result in plaque development and fragility. In this scenario, the fundamental aim of the study was to reproduce a disease model inducing vitamin D deficiency and atheromatosis in ApoE-/- mice and then to evaluate the impact of this vitamin D status on the onset/progression of atheromatosis, focusing on plaque formation and instability. Methods and Results In our murine disease model, vitamin D deficiency was achieved by 3 weeks of vitamin D deficient diet along with intraperitoneal paricalcitol injections, while atheromatosis by western-type diet. Under these experimental conditions, vitamin D deficient mice developed more unstable atheromatous plaques with reduced or absent fibrotic cap. Since calcium and phosphorus metabolism and also cholesterol and triglycerides systemic concentration were not affected by vitamin D level, our results highlighted the role of vitamin D deficiency in the formation/instability of atheromatous plaque and, although further studies are needed, suggested a possible intervention with vitamin D to prevent or delay the atheromatous disease. Conclusions The data obtained open the question about the potential role of the vitamins in the pharmacological treatments of cardiovascular disorders as coadjutant of the primary drugs used for these pathologies

Dexamethasone counteracts the anti-osteoclastic, but not the anti-leukemic, activity of TNF-related apoptosis inducing ligand (TRAIL)

We have analyzed the effect of the synthetic glucocorticoid dexamethasone, used alone or in combination with recombinant TRAIL, on in vitro osteoclastic differentiation of peripheral blood-derived macrophages cultured in the presence of macrophage-colony stimulating factor (M-CSF) + RANKL for 12-14 days. Dexamethasone exhibited different effects based on the concentration used. Indeed, while at 10(-7) M dexamethasone reduced the number of mature osteoclasts, at 10(-8) M showed no significant effects and at 10(-9) M significantly increased the number of mature osteoclasts, with respect to cells cultured with only M-CSF + RANKL. On the other hand, the addition in culture of recombinant TRAIL inhibited the output of mature osteoclasts induced by M-CSF + RANKL. However, the presence of dexamethasone (10(-8) or 10(-9) M) into the culture medium significantly counteracted the anti-osteoclastic activity of TRAIL. In order to ascertain whether dexamethasone, might also interfere with the anti-leukemic activity of TRAIL, the degree of apoptosis induced by TRAIL was evaluated in several myeloid (OCI, MOLM, HL-60) and lymphoid (SKW6.4, MAVER, BJAB) leukemic cell lines. The levels of TRAIL-triggered apoptosis were not significantly different between leukemic cells cultured in the absence or presence of dexamethasone. Concerning the molecular mechanism mediating the dexamethasone-suppression of the TRAIL activity in pre-osteoclasts, but not in leukemic cells, we found that dexamethasone induced a significant down-regulation of the surface levels of TRAIL-R2 in cells of the osteoclastic lineage but not in leukemic cells. The ability of dexamethasone to counteract the TRAIL pathway envisions a novel mechanism mediating the pro-osteoclastic activity of dexamethasone in vivo

Effects of intermittent pneumatic compression treatment on clinical outcomes and biochemical markers in patients at low mobility with lower limb edema

Objective: We aimed to evaluate the effects of intermittent pneumatic compression (IPC) in patients at low mobility with leg edema. Methods: A pilot, two-arm, randomized controlled clinical trial was performed. Fifty patients (age, 58.4 ± 9 years; male, 14), randomly allocated to a group (IPC) undergoing 1 month (n = 29) of an in-home cycle of IPC and to a control (C) group (n = 21), were studied. Leg edema was evaluated by measuring subcutaneous thickness (high-resolution ultrasound) and circumferences (metric tape), both assessed at different levels of the lower limbs, and volume (water plethysmography). Ankle range of motion (ROM, goniometer), quality of life (QoL) by the 36-Item Short Form Health Survey, and a pool of plasma inflammatory markers were also evaluated. Results: Edema significantly decreased in the IPC group (for all outcome measures, P <.0001), whereas it significantly increased in the C group (P <.0001). Ankle ROM was significantly enhanced in the IPC group (dorsiflexion, P <.0001; plantar flexion, P =.002) and remained stable in the C group. QoL showed an improvement in the IPC group, particularly significant for the general health subscale (P =.004), whereas no changes were highlighted in the C group. The two groups exhibited different trends and variations for some plasma inflammatory markers, mainly for granulocyte colony-stimulating factor. Conclusions: In a sample of patients at reduced mobility with leg edema, IPC treatment was effective in reducing the edema, improving the ankle ROM, and determining a positive impact on QoL together with a slight modulation of some plasma inflammatory markers