Immunomodulatory effects of metronomic vinorelbine (mVRL), with or without metronomic capecitabine (mCAPE), in hormone receptor positive (HR+)/HER2-negative metastatic breast cancer (MBC) patients: final results of the exploratory phase 2 Victor-5 study.

Tregs are able of suppressing tumor-specific effector cells, such as lymphocytes CD8+, CD4+ and Natural Killer cells. Different drugs, especially different schedules of administration, like metronomic chemotherapy (mCHT), seem to be able to increase anticancer immunity, by acting on downregulation of Tregs. Most of the data available regarding the immunomodulating effect of mCHT have been obtained with Cyclophosphamide (CTX). Aim of the present study was to explore the effects of mVRL and mCAPE administration, alone or in combination, on T cells. Observation of 13 metastatic breast cancer patients lasted controlling for 56 days, where Treg frequencies and function, spontaneous anti-tumor T-cell responses were monitored, as well as the clinical outcome. No depletion in Treg absolute numbers, or percentage of T lymphocytes, was observed. Only in 5 patients, a modest and transient depletion of Tregs was observed during the first 14 days of treatment. To better describe the effect on Tregs, we subsequently looked at the variations in Memory, Naïve and Activated Treg subpopulations: we observed a trend in reduction for memory Treg (Treg MEM) and an increase for Treg Naïve (Treg NAIVE) and Treg Activated (Treg ACT) components. We finally analyzed the average trend of Treg in the Treg depleted patients and non-depleted ones, without fiding any significant differences. The trend of the Treg MEM appeared different, showing a reduction during the first 14 days, followed by an increase at the levels before treatment at Day 56 in the group of depleted patients and a progressive substantial reduction in the group of non-depleted patients along the entire course of treatment. Opposed to the data known, treatment with mVRL w/o mCAPE did not show any effect on Tregs.

Role of inflammation in non-allergic rhinitis.

OBJECTIVE: To investigate the role of inflammation in non-allergic rhinitis (NAR) patients in a large series to establish the prevalence of different NAR-subtypes, clinical features and the role of nasal cytology in the diagnostic algorithm. METHODOLOGY: Patients were selected out of 3650 individuals who spontaneously presented at our institution. We consecutively enrolled 519 NAR-patients in an analytical cross-sectional study between November 2007 and June 2013 (level of evidence: 3b). All patients underwent rhinological evaluation including symptoms questionnaire, endoscopy, CT scan, allergy tests and nasal cytology. RESULTS: The inflammatory cell infiltrate affects the severity of symptoms differently, allowing for identification of different phenotypes of NAR. We distinguished two groups: "NAR without inflammation"(NAR-) and "NAR with inflammation"(NAR+), in addition to different NAR-subtypes with inflammation. A significant difference was observed in terms of clinical symptoms and association with comorbidities (previously diagnosed asthma and aspirin intolerance) between NAR­, NAR+ and between different NAR+ subtypes. CONCLUSION: Our data suggest that NAR- and NAR with neutrophils behave similarly, showing lower symptom score values and a lower risk of association with comorbidities compared to NAR with eosinophils and mast cells (singularly or mixed). In our belief it is very important to establish the presence and type of inflammation in non-allergic rhinitis patients and nasal cytology is a very useful test in correct differential diagnosis.

Relaxometric investigations and MRI evaluation of a liposome-loaded pH-responsive gadolinium(III) complex.

Accurate measurement of the tissue pH in vivo by MRI may be of clinical value for both diagnosis and selection/monitoring of therapy. To act as pH reporters, MRI contrast agents have to provide responsiveness to pH that does not require prior knowledge of the actual concentration of the contrast agent. This work deals with the use of a paramagnetic gadolinium(III) complex, loaded into liposomes, whose relaxometric properties are affected by the pH of the medium. In this system, the amphiphilic metal complex, which contains a moiety whose protonation changes the coordination properties of the metal chelate, experiences a different intraliposomial distribution depending on the pH conditions. The pH of the solution can be unambiguously identified by exploiting the peculiar characteristics of the resulting NMRD profiles, and a ratiometric pH-responsive method has been set up by comparing the relaxation enhancement at different magnetic field strengths.

Latest advancements in the pharmacological treatment of binge eating disorder.

BACKGROUND: Binge-eating disorder (BED) is a relatively new disorder characterized by binge eating without purging. AIM: The purpose of this article is to review the potential use of the recently proposed compounds for the treatment of BED. MATERIALS AND METHODS: A medline of published articles from 1980 to December 2012 was carried out using the following keywords: BED and treatment, topiramate, zonisamide, ghrelin. RESULTS: The pharmacological treatment of BED is still heterogenous and poorly established, mainly for the lack of controlled studies in large samples of patients. CONCLUSIONS: The data on serotonin and norepinephrine reuptake inhibitors and on novel anticonvulsants seem quite promising in terms of efficacy and tolerability. In addition, the preliminary findings on the possibility of modulating appetite through the interference with the ghrelin system suggest new and intriguing ways of intervention in BED.

Psychiatric disorders and mitochondrial dysfunctions.

BACKGROUND: Mitochondria play a key role in the production of the cell energy. The final product of this process is adenosine triphosphate (ATP), used as a source of chemical energy. Besides this major role, mithocondria have been shown to be involved in other functions, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. The aim of this paper is to highlight the relationships between psychiatric disorders, especially schizophrenia, bipolar disorder (BD), autism, attention deficit-hyperactivity disorder (ADHD) and Alzheimer's dementia. RESULTS: The review of the available literature indicate that different mitochondrial dysfunctions may accompany and/or be part of the clinical picture of some neuropsychiatric disorders. CONCLUSIONS: Different data would indicate that mitochondrial dysfunctions may be involved in the pathophysiology of different neuropsychiatric disorders, given their key role in the cell energy metabolism. Moreover, they would greatly contribute to the process of neural apoptosis that should be at the basis of neurodegenerative disorders, such as schizophrenia, Alzheimer's dementia and the most severe forms of BD. In addition, data are available that mithocondrial abnormalities are present also in developmental disorders, such as autism and ADHD, although the studies aiming at elucidating the role of mithocondria in the onset and pathophysiology of all these conditions should be considered preliminary. In any case, taken together, these scattered findings would suggest novel drugs targeting protecting mitochondria from oxidative stress.

Modulation of the platelet serotonin transporter by thermal balneotherapy: a study in healthy subjects.

BACKGROUND: Although the beneficial effects of balneotherapy have been recognized since a long time, a few information is available on the biological mechanisms underlying them and the subjective feelings of increased well-being and mood. AIM: The links between the serotonin (5-HT) system and mood prompted us to investigate the 5-HT platelet transporter (SERT), which is considered a reliable, peripheral marker of the same structure present in presynaptic neurons, in 30 healthy volunteers before (t0) and 30 minutes after (t1) thermal balneotherapy with ozonized water, as compared with a similar group who underwent a bath in non-mineral water. MATERIALS AN METHODS: The SERT was evaluated by means of the specific binding of 3H-paroxetine (3H-Par) to platelet membranes. Equilibrium-saturation binding data, the maximal binding capacity (Bmax) and the dissociation constant (Kd), were obtained by means of the Scatchard analysis. RESULTS: The results showed that, while Bmax values did not change in both groups, the Kd values decreased significantly at t1 only in those subjects who bathed in ozonized water. CONCLUSIONS: The results of this study, while showing a decrease of the dissociation constant (Kd) which is the inverse of affinity constant, of 3H-Par binding to SERT in all subjects after balneotherapy and not in those bathing in normal water, suggest that SERT modifications may be related to a specific effect of ozonized water and, perhaps, also to the increased sense of well-being.

Increased expression of the ectoenzyme CD38 in peripheral blood plasmablasts and plasma cells of patients with systemic sclerosis.

Objective: CD38 is a type II glycoprotein highly expressed on plasmablasts and on short- and long-lived plasma cells, but weakly expressed by lymphoid, myeloid, and non-hematopoietic cells. CD38 is a target for therapies aimed at depleting antibody-producing plasma cells. Systemic sclerosis (SSc) is an immune-mediated disease with a well-documented pathogenic role of B cells. We therefore analyzed CD38 expression in different subsets of peripheral blood mononuclear cells (PBMCs) from a cohort of SSc patients. Methods: Cell surface expression of CD38 was evaluated on PBMCs from SSc patients using eight-color flow cytometry analysis performed with a FacsCanto II (BD). Healthy individuals were used as controls (HC). Results: Forty-six SSc patients (mean age 56, range 23-79 years; 38 females and 8 males), and thirty-two age- and sex-matched HC were studied. Twenty-eight patients had the limited cutaneous form and eighteen the diffuse cutaneous form of SSc. The mean disease duration was 7 years. Fourteen patients were on immunosuppressive therapy (14 MMF, 5 RTX). The total percentages of T, B and NK cells were not different between SSc and HC. Compared to HC, SSc patients had higher levels of CD3+CD38+ T cells (p<0.05), higher percentage (p<0.001) of CD3+CD4+CD25+FOXP3+ regulatory T cells, lower percentage (p<0.05) of CD3+CD56+ NK T cells. Moreover, SSc patients had higher levels of CD24highCD19+CD38high regulatory B cells than HC (p<0.01), while the amount of CD24+CD19+CD38+CD27+ memory B cells was lower (p<0.001). Finally, the percentages of circulating CD38highCD27+ plasmablasts and CD138+CD38high plasma cells were both higher in the SSc group than in HC (p<0.001). We did not observe any correlations between these immunophenotypes and disease subsets or duration, and ongoing immunosuppressive treatment. Conclusions: The increased expression of CD38 in peripheral blood plasmablasts and plasma cells of SSc patients may suggest this ectoenzyme as a candidate therapeutic target, under the hypothesis that depletion of these cells may beneficially downregulate the chronic immune response in SSc patients. Validation of this data in multicenter cohorts shall be obtained prior to clinical trials with existing anti-CD38 drugs.

Nasal lavage CCL24 levels correlate with eosinophils trafficking and symptoms in chronic sino-nasal eosinophilic inflammation.

OBJECTIVES: The aim of our study was to measure CCL24 (eotaxin-2) levels in nasal lavage fluid of patients with different forms of sinonasal chronic eosinophilic inflammation to verify the relationship with nasal hypereosinophilia and symptoms. METHODS: Patients with nasal hypereosinophilia were randomly recruited and grouped in persistent allergic rhinitis, non-allergic rhinitis with eosinophilia syndrome (NARES) and chronic rhinosinusitis with polyps. Non rhinitic volunteers were recruited as controls. CCL24 concentration was measured by `Quantikine Human CCL24 Immunoassay`. Differential cell counts were performed by microscopic cytological examination of nasal tissue scraped by inferior turbinate. RESULTS: CCL24 levels measured in patient groups were significantly higher compared to control group with the highest levels in NARES patients. Eotaxin- 2 levels were significantly correlated to severity of symptoms and to the percentage of eosinophils in nasal tissue. CONCLUSIONS: We revealed high levels of CCL24 in all patient groups showing a significant correlation with the degree of eosinophilia and clinical symptoms. A prolonged accumulation of CCL24 inside the nasal mucosa may sustain the process of unspecific self-perpetuating eosinophil recruitment pathognomonic of these patients.

Normalisation of immune cell imbalance after pharmacological treatments of patients suffering from obsessive-compulsive disorder.

Recent data have shown the presence of immunological alterations in adult patients suffering from obsessive-compulsive disorder (OCD). The objective of this study was to examine the possible effects of 12 months of treatment with different serotonergic drugs, such as clomipramine and selective serotonin reuptake inhibitors (SSRIs) on peripheral immunological cells of 18 OCD patients. Both the absolute number and percent of CD4+, CD8+, CD3+, CD19+ and CD56+ cells were measured in peripheral blood before and after treatment by means of a Facstar Flow Sorter apparatus. At baseline, all patients showed a significant increase of CD8+ and decrease of CD4+ lymphocytes when compared with a similar group of healthy control subjects; after the treatment, CD8+ and CD4+ cells, respectively, decreased and increased significantly, and the CD4+/CD8+ ratio increased, when compared with baseline values, in parallel with the clinical improvement. These data suggest that the alterations of immune cells reported in patients with OCD at baseline may be reverted by treatment with SRIs and should be considered a state-dependent marker, perhaps related to a condition of stress.

A false positive case of high-sensitivity cardiac troponin in a patient with acute chest pain: Analytical study of the interference.

We report a case of a heterophile antibodies interference in a new high-sensitivity troponin commercial immunoassay (cTNIH Siemens), observed in a patient with possible acute coronary syndrome (ACS). The analytical interference was investigated with standard laboratories procedures. The false positive result was found with different troponin methods and kits. We also investigated the protein sequence of cTnl and no sequence variants were detected. The discordance between clinical pictures and high concentration of cTnl, together with the collaboration between clinicians and laboratory staff avoided possible erroneous diagnosis and further invasive investigations to the patient.

Anti-inflammatory activity of the extract, fractions and amides from the leaves of Piper ovatum Vahl (Piperaceae).

Leaves of Piper ovatum are known in folk medicine as "joão burandi" or "anestésica" and in traditional Brazilian medicine are used to treat inflammatory disease. The hydroalcoholic extract, fractions, and a mixture of piperovatine (1) and piperlonguminine (2) in a proportion of 2:3 obtained from Piper ovatum were assayed for anti-inflammatory activity by means of carrageenan-induced pleurisy in rats and croton oil-induced ear edema in mice. The hydroalcoholic extract was analyzed by high-performance liquid chromatography. Fraction constituents were evaluated by phytochemical screening, and the mixture of amides (1 and 2) was identified by analyses of spectral data of (1)H and (13)C nuclear magnetic resonance. Acute toxicity of the extract also was evaluated. At 500mg/kg, the hydroalcoholic extract of Piper ovatum leaves did not reduce the volume of inflammatory pleural exudates compared with control animals. However, the hydroalcoholic extract and fractions F1-F3 at doses of 5.0mg/ear and a mixture of piperovatine (1) and piperlonguminine (2) at doses of 2.5, 1.25, and 0.625mg/ear significantly reduced the degree of ear edema. Taken together, the results indicate that the amide fractions piperovatine and piperlonguminine showed the greatest inhibitory activity of topical inflammation induced by croton oil.

Very unusual "needle- and pencil-like" uric acid crystals in the urine unmasked by infrared spectroscopy investigation.

In this paper we describe a case with very unusual "needle- and pencil-like" crystals, partly similar to those reported by other investigators, who considered them as due to uric acid. Quite importantly, infrared spectroscopy investigation which, to our knowledge, we have been the first to perform on this type of crystals, confirmed their nature as uric acid structures. This case demonstrates that the planet of urinary crystals still has several unknown facets and still deserves exploration.

Procalcitonin is useful in driving the choice of early antibiotic treatment in patients with bloodstream infections.

OBJECTIVE: To evaluate whether PCT levels could be used to distinguish among different bacterial and fungal etiologies in patients with documented bloodstream infection (BSI). PATIENTS AND METHODS: Monocentric retrospective cohort study on patients admitted to the Fondazione Policlinico Gemelli Hospital between December 2012 and November 2015 with BSI. Those who had undergone PCT determination within 48 hours of when the first positive blood culture was sampled were included in the study. RESULTS: Four hundred and one patients were included in the study. Both the 24h and 48h PCT values were significantly higher in patients with Gram-negative (GN) BSI than in those with Gram-positive (GP) or candida BSI (p at ANOVA = 0.003). A PCT value of > 1 ng/ml was found in 31.5% of patients with GN BSI. Less than 7% of people with candida BSI had PCT level of > 1 ng/ml. At multivariable regression analysis, GN BSI, septic shock, and plasma creatinine were significantly correlated with PCT values. CONCLUSIONS: PCT may be of value in distinguishing GN BSI from GP, and fungal BSI and PCT values of > 1 ng/ml could be used to prevent unnecessary antifungal treatment.

Advanced capabilities for materials modelling with Quantum ESPRESSO.

Quantum EXPRESSO is an integrated suite of open-source computer codes for quantum simulations of materials using state-of-the-art electronic-structure techniques, based on density-functional theory, density-functional perturbation theory, and many-body perturbation theory, within the plane-wave pseudopotential and projector-augmented-wave approaches. Quantum EXPRESSO owes its popularity to the wide variety of properties and processes it allows to simulate, to its performance on an increasingly broad array of hardware architectures, and to a community of researchers that rely on its capabilities as a core open-source development platform to implement their ideas. In this paper we describe recent extensions and improvements, covering new methodologies and property calculators, improved parallelization, code modularization, and extended interoperability both within the distribution and with external software.

Ionizing radiation: brain effects and related neuropsychiatric manifestations. / IONIZUIuChA RADIATsIIa: VPLYV NA GOLOVNYY̆ MOZOK TA NEY̆ROPSYKhIATRYChNI PROIaVY.

Recently, an increasing interest has been directed towards the investigation of brain effects of ionizing radiation (IR), as it is now evident that, depending on the doses, the damages character and severity, as well as clinical man ifestations are different. They are generally considered to be the result of a blending of atherosclerotic, cardiovas cular, cerebrovascular and neurodegenerative processes. Further, an ongoing debate has been opened on the pos sible brain abnormalities following medical radiation from X ray in interventional radiology and nuclear medicine procedures that would involve both patients and medical workers. The aim of the present paper is to summarize literature data on brain effects of IR exposure, with a special focus on those gathered by some of the authors after the Chornobyl nuclear plant disaster, and how they can be related to the pathophysiology of different neuropsy chiatric disorders.

Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts.

It is established that the interaction between microenvironment and cancer cells has a critical role in tumor development, given the dependence of neoplastic cells on stromal support. However, how this communication promotes the activation of normal (NFs) into cancer-associated fibroblasts (CAFs) is still not well understood. Most microRNA (miRNA) studies focused on tumor cell, but there is increasing evidence of their involvement in reprogramming NFs into CAFs. Here we show that miR-9, upregulated in various breast cancer cell lines and identified as pro-metastatic miRNA, affects the properties of human breast fibroblasts, enhancing the switch to CAF phenotype, thus contributing to tumor growth. Expressed at higher levels in primary triple-negative breast CAFs versus NFs isolated from patients, miR-9 improves indeed migration and invasion capabilities when transfected in immortalized NFs; viceversa, these properties are strongly impaired in CAFs upon miR-9 inhibition. We also demonstrate that tumor-secreted miR-9 can be transferred via exosomes to recipient NFs and this uptake results in enhanced cell motility. Moreover, we observed that this miRNA is also secreted by fibroblasts and in turn able to alter tumor cell behavior, by modulating its direct target E-cadherin, and NFs themselves. Consistently with the biological effects observed, gene expression profiles of NFs upon transient transfection with miR-9 show the modulation of genes mainly involved in cell motility and extracellular matrix remodeling pathways. Finally, we were able to confirm the capability of NFs transiently transfected with miR-9 to promote in vivo tumor growth. Taken together, these data provide new insights into the role of miR-9 as an important player in the cross-talk between cancer cells and stroma.

Synergistic modulation by chloride and organic phosphates of hemoglobin from bear (Ursus arctos).

The oxygen binding properties of hemoglobin (Hb) from brown bear (Ursus arctos) have been studied focussing on the effect of heterotropic ligands, and the behaviour has been compared with that of human HbA, taken as a prototype of mammalian Hbs. It has been observed that in bear Hb chloride ions and 2,3-diphosphoglyceric acid (Gri(2,3)P2) can modulate the oxygen affinity in a synergistic way such that their individual effect is enhanced whenever they are both present in saturating amounts. The thermodynamic analysis of such a feature indicates that in bear Hb there are two classes of chloride binding sites, one acting synergistically with Gri(2,3)P2 and another one, which likely overlaps with the organic phosphate interaction cleft, and is therefore fully operative only in the absence of Gri(2,3)P2. The behaviour of the last site is similar to that observed in human HbA, where the effect of Cl- and Gri(2,3)P2 is mutually exclusive. The interaction energy between chloride and Gri(2,3)P2 synergistic binding sites appears to be O2-linked so that the interplay may have a relevant physiological role in modulating the oxygen transport in brown bear. This behaviour is associated with a marked pH-dependence of the oxygenation enthalpy in bear Hb, such that under acidotic and hypercloruremic conditions, oxygen supply to peripheral tissues could be maintained essentially unaltered even under low temperature conditions.

Soluble urokinase-type plasminogen activator receptor as a putative marker of male accessory gland inflammation.

UNLABELLED: The association between male accessory gland infection/inflammation (MAGI) and infertility is well-known in clinical practice. Standard semen analysis, leukocytospermia, and microbiological tests are often not enough accurate for a diagnosis. A large amount of biochemical parameters in seminal plasma have been suggested as inflammation markers, however, there is not yet a sensitive and specific biomarker that accurately identifies MAGI. We investigated the presence of soluble urokinase-type plasminogen activator receptor (suPAR), known marker of systemic inflammation, in the seminal plasma to evaluate its possible involvement in urogenital tract inflammation. On the basis of andrological evaluation, including spermiogram and ultrasound findings, we selected 76 patients with MAGI and 30 healthy men as control group. Patients were classified according to the results of the semen culture in group A (n = 28) presenting a bacterial MAGI and group B (n = 48) with abacterial MAGI. C-reactive protein (CRP), total protein (TP), procalcitonin (PCT), leukocytes peroxidase (LP), and suPAR concentrations were assayed on seminal plasma. Spermiogram parameters were significantly lower in the patients with MAGI than in controls. CRP, TP, PCT, and LP did not differ in MAGI vs. CONTROLS: suPAR was detectable in all semen samples; it was significantly increased in A and B groups (86.6 ± 30.7 ng/mL vs. 39.7 ± 17.2 ng/mL) with an inverse correlation with sperm parameters. We selected by receiver operating characteristic curve a suPAR cut-off value of 55.3 ng/mL as a diagnostic threshold for the diagnosis of MAGI. We report in this study the first evidence of suPAR presence in seminal plasma, focusing on its interesting role as reliable and sensitive marker of inflammation for the differential diagnosis of MAGI.

Dietary restriction affects antioxidant levels in rat liver mitochondria during ageing.

Six experimental groups of young (7-month-old) and aged (24-32-month-old) rats, underwent different dietary manipulations (i.e. dietary restriction and/or a vitamin E-depleted diet), and their liver mitochondria were assayed for several antioxidants and peroxidation markers. Glutathione levels were affected both by age and dietary treatment. Coenzyme Q9 and C0Q10 showed the highest levels in the oldest rats where ageing, as well as other oxidative stresses, could induce ubiquinone biosynthesis.

Coenzyme Q homologs and vitamin E in synaptic and non-synaptic occipital cerebral cortex mitochondria in the ageing rat.

The coenzyme Q8 (CoQ8) and alpha-tocopherol contents of different mitochondrial fractions were investigated from occipital cerebral cortices of different ages. The highest CoQ8 and vitamin E concentrations were found in non-synaptic free mitochondria (FM) fractions. In several cases heavy mitochondria (HM) fractions displayed the lowest values. Occipital cerebral cortex mitochondria contained higher CoQ9 and lower CoQ10 amounts than those typical for other brain regions.