Tumor microenvironment in diffuse large B-cell lymphoma: Matrixmetalloproteinases activation is mediated by osteopontin overexpression.

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative malignancies with variable patterns of behavior and responses to therapy. NHL development and invasion depend on multiple interactions between tumor cells and non-neoplastic cells. Such interactions are usually modulated by several cytokines. Accordingly, it was demonstrated that matrix-metalloproteinase (MMP)-2 and MMP-9 were activated in human lymphoid cell lines by interleukin-6 (IL-6). The activation of these enzymes is associated with tumor invasion and metastasis in human cancers. MMPs are also activated in several cancers by osteopontin (OPN), a secreted glycoprotein that regulates cell adhesion, migration, and survival. However, it is still unclear if MMPs play a role in NHL development and if their activation is determined by OPN and/or IL-6. In the present study, two groups of 78 NHL patients and 95 healthy donors were recruited for the analysis of OPN, MMP-2, MMP-9 and IL-6.Significant higher circulating levels of MMP-2, MMP-9, OPN and IL-6 were observed in NHL patients when compared to healthy donors. Similar data were obtained by analyzing the activity of both MMP-2 and MMP-9. The multivariate regression model indicates that, in both NHL cases and healthy donors, OPN is associated with the increase of MMP-2 and MMP-9 levels independently of IL-6. These data were first confirmed by "in silico" analyses and then by "in vitro" experiments conducted on peripheral blood mononuclear cells randomly selected from both NHL patients and healthy donors.Overall, our data suggest that the activation of MMPs in NHL development is mostly associated with OPN. However, IL-6 may play an important role in the lymphomagenesis through the activation of other molecular pathways. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

IL-6-174 G > C and MMP-9-1562 C > T polymorphisms are associated with increased risk of deep vein thrombosis in cancer patients.

BACKGROUND: A growing body of evidence shows an increased risk of deep vein thrombosis (DVT) among cancer patients. Novel markers are needed to identify patients prone to develop DVT. The aim of the present study was to determine whether IL-6-174 G > C and MMP-9-1562 C > T polymorphisms may influence the development of DVT in cancer patients. METHODS: Polymorphisms of IL-6 and MMP-9 were analyzed in 320 DNA samples from cancer patients (DVT+ and DVT-) and in 215 healthy donors. IL-6 and MMP-9 plasma levels were also measured by ELISA. RESULTS: Distribution of -174 IL-6 genotype and -1562 MMP-9 were similar between healthy controls and DVT- cancer cases (OR = 0.98 and 1.04, respectively). Different results were obtained by compared healthy controls with DVT+ cancer patients. -174 IL-6 GG polymorphism was associated to DVT (OR = 2.07; 95% CI: 1.30-3.30), as well as -1562 MMP-9 CC polymorphism (OR = 2.60; 95% CI: 1.48-4.57). CONCLUSION: The results of the present study support a model in which the GG and CC genotypes, respectively for IL-6-174 G > C and MMP-9-1562 C > T polymorphisms, are associated with a risk of DVT in cancer patients by inducing the release of IL-6 with subsequent increment of MMP-9. Overall, these findings may contribute to the management of DVT in cancer patients.

PAHs in seafood from the Mediterranean Sea: An exposure risk assessment.

Seafood represent an important food source for human, and seafood quality is associated with marine environment quality. PAHs are one of the main organic environmental contaminants and they can be introduced into the body through different way (ingestion, inhalation, dermal absorption). We present data on bioaccumulation of the sixteen PAHs, defined priority by the U.S.- EPA, in Sardina pilchardus, Solea solea and Donax trunculus, three species caught in the Catania Gulf and highly consumed by the local population. The risk to develop chronic systemic and carcinogenic effects due to the consumption of these target species was evaluated through the EDI, THQ and CR. EDI derived from D. trunculus ingestion falls within the range calculated by the EFSA. The THQ is less than 1, and the CR calculated for the Benzo(a)Pyrene is at the limit of the ARL (1✕10-5). EDI derived from S. pilchardus and S. solea ingestion are below the range calculated by the EFSA. The THQ is less than 1, and the CR is below the acceptable risk level. The contamination level found in local seafood determines a low risk to develop chronic systemic effects, but the cancer risk could be of health concern especially for high-frequency molluscs consumers.

Oxidative stress, nitric oxide, endothelial dysfunction and tinnitus.

To assess whether pathogenic endothelial dysfunction is involved in acute idiopathic tinnitus we enrolled 44 patients and 25 healthy volunteers. In blood from the internal jugular vein and brachial vein we determined malonaldehyde, 4-hydroxynonenal, myeloperoxidase, glutathione peroxidase, nitric oxide, L-arginine and L-ornitine, thrombomodulin (TM) and von Willebrand factor (vWF) activity during tinnitus and asymptomatic period. Higher plasma concentrations of oxidative markers and L-arginine, and lower nitric oxide and L-ornitine levels were observed in jugular blood of patients with tinnitus, there being a significant difference between brachial and jugular veins. TM and vWF activity were significantly higher in patients' jugular blood than in brachial blood. Our results suggest oxidant, TM, vWF activity production are increased and nitric oxide production reduced in brain circulation reflux blood of patients with acute tinnitus. These conditions are able to cause a general cerebro-vascular endothelial dysfunction, which in turn induce a dysfunction of microcirculation in the inner ear.

Analysis of interleukin (IL)-1beta IL-1 receptor antagonist, soluble IL-1 receptor type II and IL-1 accessory protein in HCV-associated lymphoproliferative disorders.

Hepatitis C virus (HCV) causes hepatitis, liver cirrhosis and hepatocellular carcinoma, and may also induce type II mixed cryoglobulinemia syndrome (MC), a disease characterized by clonal B-cell lymphoproliferations that can evolve into non-Hodgkin's lymphoma (NHL). Interleukin-1 (IL-1) is a cytokine that plays an important role in initiating the cascade of events of immunoinflammatory responses through costimulation of T lymphocytes, B-cell proliferation, induction of adhesion molecules and stimulation of the production of other inflammatory cytokines. The role of IL-1 in immunoinflammatory responses is highlighted by the presence of endogenous regulators (IL-1 receptor antagonist, soluble receptors type 1 and II, human IL-1 accessory protein) that, when secreted into the blood stream may serve as endogenous regulators of IL-1 action. The aim of this study was to evaluate whether abnormalities in the blood levels of IL-1beta IL-1 receptor antagonist, soluble IL-1 receptor type II and human IL-1 accessory protein in HCV+ patients are associated with development of MC and/or NHL. Relative to healthy controls, we observed: i) an increase in the circulating levels of IL-1beta in HCV+ patients simultaneously affected by NHL; ii) increased levels of IL-1 accessory protein in patients singly infected by HCV; iii) increase of IL-1 receptor antagonist in HCV+ patients and in those affected also by NHL with or without MC; iv) a homogeneous increase of sIL-1R type II in all the subgroup of patients. These data indicate that an attempt to increased circulating levels of IL-1 inhibitors occurs at different extent in the course of HCV infection as well as in its progression to NHL and/or MC.

Expression of DNA methylation genes in secondary progressive multiple sclerosis.

Multiple sclerosis (MS) is an immunoinflammatory disease of the central nervous system that seems to be influenced by DNA methylation. We sought to explore the expression pattern of genes involved in the control of DNA methylation in Secondary Progressive (SP) MS patients' PBMCs. We have found that SP MS is characterized by a significant upregulation of two genes belonging to the MBD family genes, MBD2 and MBD4, and by a downregulation of TDG and TET3.

Relationship between carotid intima-media thickness and non valvular atrial fibrillation type.

OBJECTIVE: Carotid intima-media thickness (cIMT) is a surrogate marker of subclinical atherosclerosis and it is able to predict both coronary and cerebral vascular events. No data exist on the association between cIMT and non valvular atrial fibrillation (NVAF) type. We conduct this study with the aim to analyze the association between abnormal cIMT and NVAF type. METHODS: A cross-sectional study of the "Atrial fibrillation Registry for Ankle-brachial index Prevalence Assessment-Collaborative Italian Study (ARAPACIS)" has been performed. Among 2027 patients enrolled in the ARAPACIS, 673 patients, who underwent carotid ultrasound examination to assess cIMT, were included in the study. RESULTS: Among the entire population, 478 patients (71%) had cIMT > 0.90 mm. Patients with an abnormal cIMT (>0.90 mm) were significantly older and more likely hypertensive, diabetic and with a previous history of stroke than those with normal cIMT (≤0.90 mm). These patients had more permanent/persistent NVAF and CHA2DS2-VASc score ≥ 2 (p < 0.0001) compared to those with cIMT <0.90 mm. Excluding all patients affected by previous cardiovascular disease, logistic regression analysis showed that independent predictors of abnormal cIMT were: age class 65-74 yrs. (p < 0.001), age class ≥75 yrs. (p < 0.001), arterial hypertension (p < 0.001), calcium-channel blockers use (p < 0.001) and persistent/permanent NVAF (p = 0.001). CONCLUSION: Our findings show a high prevalence of abnormal cIMT in NVAF patients, reinforcing the concept that NVAF and systemic atherosclerosis are closely associated. Abnormal cIMT was particularly evident in persistent/permanent NVAF suggesting a more elevated atherosclerotic burden in patients with long-standing NVAF. TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT01161251.

Roles of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer.

Cancer remains one of the major cause of death in the Western world. Although, it has been demonstrated that new therapies can improve the outcome of cancer patients, still many patients relapse after treatment. Therefore, there is a need to identify novel factors involved in cancer development and/or progression. Recently, neutrophil gelatinase-associated lipocalin (NGAL) has been suggested as a key player in different cancer types. Its oncogenic effect may be related to the complex NGAL/MMP-9. In the present study, NGAL was analyzed at both transcript and protein levels in different cancer types by analysing 38 public available microarray datasets and the Human Protein Atlas tool. NGAL transcripts were significantly higher in the majority of solid tumors compared to the relative normal tissues for every dataset analyzed. Furthermore, concordance of NGAL at both mRNA and protein levels was observed for 6 cancer types including bladder, colorectal, liver, lung, ovarian, and pancreatic. All metastatic tumors showed a decrease of NGAL expression when compared to matched primary lesions. According to these results, NGAL is a candidate marker for tumor growth in a fraction of solid tumors. Further investigations are required to elucidate the function of NGAL in tumor development and metastatic processes.