CXCL16/CXCR6 axis drives microglia/macrophages phenotype in physiological conditions and plays a crucial role in glioma

Microglia are patrolling cells that sense changes in the brain microenvironment and respond acquiring distinct phenotypes that can be either beneficial or detrimental for brain homeostasis. Anti-inflammatory microglia release soluble factors that might promote brain repair; however, in glioma, anti-inflammatory microglia dampen immune response and promote a brain microenvironment that foster tumor growth and invasion. The chemokine CXCL16 is expressed in the brain, where it is neuroprotective against brain ischemia, and it has been found to be over-expressed in glioblastoma (GBM). Considering that CXCL16 specific receptor CXCR6 is diffusely expressed in the brain including in microglia cells, we wanted to investigate the role of CXCL16 in the modulation of microglia cell activity and phenotype, and in the progression of glioma. Here we report that CXCL16 drives microglia polarization toward an anti-inflammatory phenotype, also restraining microglia polarization toward an inflammatory phenotype upon LPS and IFN? stimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation toward an anti-inflammatory/pro-tumor phenotype, and that cxcr6ko mice, orthotopically implanted into the brain with GL261 glioma cells,survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on mouse glioma cells, as well as human primary GBM cells, promoting tumor cell growth, migration and invasion. All together these data suggest that CXCL16 signaling could represent a good target to modulate microglia phenotype in order to restrain inflammation or to limit glioma progression

Comment on: Hemodiafiltration in a critical dialysis patient with H1N1 influenza A

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KCa3.1 channel inhibition sensitizes malignant gliomas to temozolomide treatment

Malignant gliomas are among the most frequent and aggressive cerebral tumors, characterized by high proliferative and invasive indexes. Standard therapy for patients, after surgery and radiotherapy, consists of temozolomide (TMZ), a methylating agent that blocks tumor cell proliferation. Currently, there are no therapies aimed at reducing tumor cell invasion. Ion channels are candidate molecular targets involved in glioma cell migration and infiltration into the brain parenchyma. In this paper we demonstrate that: i) blockade of the calcium-activated potassium channel KCa3.1 with TRAM-34 has co-adjuvant effects with TMZ, reducing GL261 glioma cell migration, invasion and colony forming activity, increasing apoptosis, and forcing cells to pass the G2/M cell cycle phase, likely through cdc2 de-phosphorylation; ii) KCa3.1 silencing potentiates the inhibitory effect of TMZ on glioma cell viability; iii) the combination of TMZ/TRAM-34 attenuates the toxic effects of glioma conditioned medium on neuronal cultures, through a microglia dependent mechanism since the effect is abolished by clodronate-induced microglia killing; iv) TMZ/TRAM-34 co-treatment increases the number of apoptotic tumor cells, and the mean survival time in a syngeneic mouse glioma model (C57BL6 mice implanted with GL261 cells); v) TMZ/TRAM-34 co-treatment reduces cell viability of GBM cells and cancer stem cells (CSC) freshly isolated from patients.Taken together, these data suggest a new therapeutic approach for malignant glioma, targeting both glioma cell proliferating and migration, and demonstrate that TMZ/TRAM-34 co-treatment affects both glioma cells and infiltrating microglia, resulting in an overall reduction of tumor cell progression

Sevelamer carbonate in the treatment of hyperphosphatemia in patients with chronic kidney disease on hemodialysis

Sevelamer carbonate is an anion exchange pharmaceutical, developed to improve on the performance of the non-absorbable, non-calcium, and metal-free phosphate binder sevelamer hydrochloride. Sevelamer carbonate is expected not to worsen metabolic acidosis, as previously reported during long-term treatment with sevelamer hydrochloride in hemodialysis (HD) patients. Carbonate is the alternate counterion to chloride on the sevelamer polymeric backbone, but the active poly(allylamine) responsible for phosphate (PO4) binding remains unaltered. Therefore, sevelamer carbonate is expected to reduce elevated serum phosphorus level, similarly to sevelamer hydrochloride. Sevelamers are prescribed in uremic HD patients to control hyperphosphatemia, but the carbonate has also been proposed for the treatment of chronic kidney disease (CKD) non-dialysis patients. Although hyperphosphatemia is regarded as a main contributor to increased mortality in the HD population because of cardiovascular calcification, metabolic acidosis has also been advocated as a major player in the increased mortality in this population, by engendering malnutrition, negative nitrogen balance, and inflammation. This paper reviews the evidence showing that sevelamer carbonate is as good as sevelamer hydrochloride in terms of hyperphosphatemia control in CKD, but with a better outcome in serum bicarbonate balance

Hyperhomocysteinemia and C677T MTHFR genotype in patients with retinal vein thrombosis.

Introduction: Elevated homocysteine (Hcy) is associated with the risk of deep vein thrombosis, pulmonary embolism, ischemic heart disease, and stroke. Several studies have suggested that hyperhomocysteinemia (HHcy) may predispose to retinal vein thrombosis (RVT) development. The aim of this study is to investigate the relationship between Hcy, C677T methylenetetrahydrofolate reductase (MTHFR) genotype, and RVT in patients compared with controls. Materials and Methods: We evaluated the Hcy plasma level of 3114 consecutive participants in 2 Italian centers during a 2-year period. Hyperhomocysteinemia was found in 99 patients and 136 healthy participants. Of the 99 patients, 20 had RVT with a high prevalence of HHcy in the RVT subgroup (20.2%). This result suggested a possible relationship between HHcy and RVT development. We investigated 105 consecutive patients with recent diagnosis of RVT, and we compared them with 226 healthy controls to evaluate whether HHcy may be a risk factor for RVT. Results: the prevalence of HHcy was higher in patients compared with controls (34.3% vs 14.2%; P < .001). The MTHFR C677T genotype was found in 69 of 105 (65.7%) patients with RVT (heterozygosity: 40 of 105 and homozygosity: 29 of 105). The control group showed the presence of MTHFR C677T genotype in 169 of 226 participants (74.8%; heterozygosity: 100 of 226 and homozygosity: 69 of 226) without difference between the 2 groups (P = .08). Conclusion: our study suggests that HHcy is a possible risk factor for RVT development, while no association was found between RVT and the C677T MTHFR genotype

Cardiovascular Issues in Tyrosine Kinase Inhibitors Treatments for Chronic Myeloid Leukemia: A Review

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by a fusion gene, encoding for the chimeric protein BCR-ABL, with constitutive tyrosine kinase activity. The use of tyrosine kinase inhibitors (TKIs) has drastically improved survival, but there are significant concerns about cardiovascular toxicity. Cardiovascular risk can be lowered with appropriate baseline evaluation, accurate choice of TKI therapy, improvement of modifiable cardiovascular risk factors through lifestyle modifications, and prescription of drugs for primary or secondary prevention. Which examinations are necessary, and when do they have to be scheduled? How often should a TKI-treated patient undergo which cardiology test or exam? Is there an accurate way to estimate the risk that each TKI may determine a cardiovascular adverse event in a CML patient? In a few words, how can we optimize the cardiovascular risk management in CML patients before and during TKI treatment? The aim of this review is to describe cardiac and vascular toxicity of TKIs used for CML treatment according to the most recent literature and to identify unmet clinical needs in cardiovascular risk management and complications in these patients. Regarding the TKI-induced cardiovascular toxicity, the full mechanism is still unclear, but it is accepted that different factors may play different roles: endothelial damage and atherosclerosis, metabolic impairment, hypertensive effect, glomerular impairment, and mast-cell disruption. Preventive strategies are aimed at minimizing cardiovascular risk when CML is diagnosed. Cardio-oncology units in specialized hematology centers may afford a personalized and multidisciplinary approach to the patient, optimizing the balance between treatment of the neoplasm and management of cardiovascular risk

Real-time PCR detection of Toxoplasma gondii in tissue samples of wild boars (Sus scrofa) from southern Italy reveals high prevalence and parasite load.

Background: Toxoplasmosis is a zoonotic parasitic disease caused by Toxoplasma gondii, a widespread protozoan in the phylum Apicomplexa. In Europe, several studies have demonstrated the presence of the parasite in tissues of wild boars (Sus scrofa), but no data exists on the T. gondii load in tissues which in turn may be an useful way to assess the infection risk for the consumer of wild boar meat. Methods: We sampled and tested a total of 472 tissue samples of brain, heart and masseter muscle from 177 wild boars from the Campania region of southern Italy by real-time PCR analyses for detection and quantification of T. gondii. The sensitivity and specificity of the method were calculated by ROC analysis curves. Results: PCR analysis revealed the presence of T. gondii in tissue samples of 78 out of 177 (44%) wild boars. In general, the brain presented the highest PCR prevalence (31%), followed by the heart (28.3%) and the masseter muscle (24.2%), with the highest estimated parasite numbers observed in the brain followed by the heart and masseter muscle. The PCR method showed an excellent discriminating ability for each of the examined tissues. According to the ROC analysis curves, the respective sensitivity and specificity were 99 and 100% for masseter muscle, 98 and 98% for brain and 96 and 98% for heart samples. Conclusions: The high prevalence of infection here detected suggests a widespread distribution of the parasite in the wildlife of the Campania region of southern Italy. The T. gondii burdens detected may potentially represent a source of infection for humans

Angiostrongylus vasorum infection in red foxes (Vulpes vulpes) in southern Italy

Angiostrongylus vasorum (Nematoda: Angiostrongylidae) infection was detected at post-mortem examination in the pulmonary arteries and hearts of 34/102 (33,3%) of red foxes (Vulpes vulpes) from the Campania Region in southern Italy. Pathological changes consisted of granulomatous interstitial pneumonia caused by larvae and intravascular pulmonary adult nematodes. These changes confirm that angiostrongylosis infection in red foxes has a mainly chronic course, in which the infected host may disperse parasite larvae in the environment over its lifetime. Results suggest that the life cycle of A. vasorum is well established in the red fox in the Campania Region representing a potential infection risk for dogs

Pareto optimality in multilayer network growth

We model the formation of multi-layer transportation networks as a multi-objective optimization process, where service providers compete for passengers, and the creation of routes is determined by a multi-objective cost function encoding a trade-off between efficiency and competition. The resulting model reproduces well real-world systems as diverse as airplane, train and bus networks, thus suggesting that such systems are indeed compatible with the proposed local optimization mechanisms. In the specific case of airline transportation systems, we show that the networks of routes operated by each company are placed very close to the theoretical Pareto front in the efficiency-competition plane, and that most of the largest carriers of a continent belong to the corresponding Pareto front. Our results shed light on the fundamental role played by multi-objective optimization principles in shaping the structure of large-scale multilayer transportation systems, and provide novel insights to service providers on the strategies for the smart selection of novel routes