Showing papers by "University of Turin published in 2002"

European prospective investigation into cancer and nutrition (EPIC): study populations and data collection

Abstract: The European Prospective Investigation into Cancer and Nutrition (EPIC) is an ongoing multi-centre prospective cohort study designed to investigate the relationship between nutrition and cancer, with the potential for studying other diseases as well. The study currently includes 519 978 participants (366 521 women and 153 457 men, mostly aged 35-70 years) in 23 centres located in 10 European countries, to be followed for cancer incidence and cause-specific mortality for several decades. At enrollment, which took place between 1992 and 2000 at each of the different centres, information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire addressing usual diet. Anthropometric measurements were performed and blood samples taken, from which plasma, serum, red cells and buffy coat fractions were separated and aliquoted for long-term storage, mostly in liquid nitrogen. To calibrate dietary measurements, a standardised, computer-assisted 24-hour dietary recall was implemented at each centre on stratified random samples of the participants, for a total of 36 900 subjects. EPIC represents the largest single resource available today world-wide for prospective investigations on the aetiology of cancers (and other diseases) that can integrate questionnaire data on lifestyle and diet, biomarkers of diet and of endogenous metabolism (e.g. hormones and growth factors) and genetic polymorphisms. First results of case-control studies nested within the cohort are expected early in 2003. The present paper provides a description of the EPIC study, with the aim of simplifying reference to it in future papers reporting substantive or methodological studies carried out in the EPIC cohort.

A Human Genome Diversity Cell Line Panel

Abstract: A resource of 1064 cultured lymphoblastoid cell lines (LCLs) ([1][1]) from individuals in different world populations and corresponding milligram quantities of DNA is deposited at the Foundation Jean Dausset (CEPH) ([2][2]) in Paris. LCLs were collected from various laboratories by the Human Genome

Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.

Abstract: PURPOSE: To evaluate whether two commonly used newer platinum-based regimens offer any advantage over vinorelbine-cisplatin (reference regimen) in response rate for patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients were randomized to receive gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 2 every 21 days (GC arm), or paclitaxel 225 mg/m2 (3-hour infusion) then carboplatin (area under the concentration-time curve of 6 mg/mL·min), both on day 1 every 21 days (PCb arm), or vinorelbine 25 mg/m2/wk for 12 weeks then every other week plus cisplatin 100 mg/m2 day 1 every 28 days (VC arm). RESULTS: Six hundred twelve patients were randomized to treatment (205 GC, 204 PCb, and 203 VC). Overall response rates for the GC (30%) and PCb (32%) arms were not significantly different from that of the VC arm (30%). There were no differences in overall survival, time to disease progression, or time to treatment failure. Median survival for the GC, P...

The BABAR detector

Abstract: BABAR, the detector for the SLAC PEP-II asymmetric e+e- B Factory operating at the upsilon 4S resonance, was designed to allow comprehensive studies of CP-violation in B-meson decays. Charged particle tracks are measured in a multi-layer silicon vertex tracker surrounded by a cylindrical wire drift chamber. Electromagentic showers from electrons and photons are detected in an array of CsI crystals located just inside the solenoidal coil of a superconducting magnet. Muons and neutral hadrons are identified by arrays of resistive plate chambers inserted into gaps in the steel flux return of the magnet. Charged hadrons are identified by dE/dx measurements in the tracking detectors and in a ring-imaging Cherenkov detector surrounding the drift chamber. The trigger, data acquisition and data-monitoring systems, VME- and network-based, are controlled by custom-designed online software. Details of the layout and performance of the detector components and their associated electronics and software are presented.

Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT

Abstract: Ghrelin is an acyl-peptide gastric hormone acting on the pituitary and hypothalamus to stimulate growth hormone (GH) release, adiposity, and appetite. Ghrelin endocrine activities are entirely dependent on its acylation and are mediated by GH secretagogue (GHS) receptor (GHSR)-1a, a G protein-coupled receptor mostly expressed in the pituitary and hypothalamus, previously identified as the receptor for a group of synthetic molecules featuring GH secretagogue (GHS) activity. Des-acyl ghrelin, which is far more abundant than ghrelin, does not bind GHSR-1a, is devoid of any endocrine activity, and its function is currently unknown. Ghrelin, which is expressed in heart, albeit at a much lower level than in the stomach, also exerts a cardio protective effect through an unknown mechanism, independent of GH release. Here we show that both ghrelin and des-acyl ghrelin inhibit apoptosis of primary adult and H9c2 cardiomyocytes and endothelial cells in vitro through activation of extracellular signal-regulated kinase-1/2 and Akt serine kinases. In addition, ghrelin and des-acyl ghrelin recognize common high affinity binding sites on H9c2 cardiomyocytes, which do not express GHSR-1a. Finally, both MK-0677 and hexarelin, a nonpeptidyl and a peptidyl synthetic GHS, respectively, recognize the common ghrelin and des-acyl ghrelin binding sites, inhibit cell death, and activate MAPK and Akt.These findings provide the first evidence that, independent of its acylation, ghrelin gene product may act as a survival factor directly on the cardiovascular system through binding to a novel, yet to be identified receptor, which is distinct from GHSR-1a.

Scatter-factor and semaphorin receptors: cell signalling for invasive growth

Abstract: Malignant disease occurs when neoplastic cells abandon their primary site of accretion, cross tissue boundaries and penetrate the vasculature to colonize distant sites. This process --metastasis--is the aberrant counterpart of a physiological programme for organ regeneration and maintenance. Scatter factors and semaphorins, together with their receptors, help to orchestrate this programme. What are the differences between physiological and pathological activation of these signalling molecules, and can we exploit them therapeutically to prevent metastasis?

Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response

Abstract: Pentraxins are a superfamily of conserved proteins that are characterized by a cyclic multimeric structure1. The classical short pentraxins, C-reactive protein (CRP) and serum amyloid P component (SAP), are acute-phase proteins produced in the liver in response to inflammatory mediators2,3,4. Short pentraxins regulate innate resistance to microbes and the scavenging of cellular debris and extracellular matrix components2,3,4,5. In contrast, long pentraxins have an unrelated, long amino-terminal domain coupled to the carboxy-terminal pentraxin domain, and differ, with respect to short pentraxins, in their gene organization, chromosomal localization, cellular source, and in their stimuli-inducing and ligand-recognition ability6. To investigate the in vivo function of the long pentraxin PTX3, we generated mice deficient in Ptx3 by homologous recombination. Ptx3-null mice were susceptible to invasive pulmonary aspergillosis. Ptx3 binds selected microbial agents, including conidia of Aspergillus fumigatus, and we found that susceptibility of Ptx3-null mice was associated with defective recognition of conidia by alveolar macrophages and dendritic cells, as well as inappropriate induction of an adaptive type 2 response. Thus, the long pentraxin Ptx3 is a secreted pattern-recognition receptor that has a non-redundant role in resistance to selected microbial agents, in particular to the opportunistic fungal pathogen Aspergillus fumigatus.

Abundant Tau Filaments and Nonapoptotic Neurodegeneration in Transgenic Mice Expressing Human P301S Tau Protein

Abstract: The identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments of Alzheimer's disease Sarkosyl-insoluble tau from brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa band, the same apparent molecular mass as that of the 383 aa tau isoform in the human tauopathies Perchloric acid-soluble tau was also phosphorylated at many sites, with the notable exception of serine 214 In the spinal cord, neurodegeneration was present, as indicated by a 49% reduction in the number of motor neurons No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members The latter may be involved in the hyperphosphorylation of tau

Biological invasion risks and the public good: an economic perspective

Abstract: We postulate that the causes of the problem of invasive alien species are primarily economic and, as such, require economic solutions. Invasive alien species are of increasing concern for four reasons. First, introductions are increasing sharply, while mechanisms for excluding or eradicating alien species have been either withdrawn or progressively weakened. Both trends are due to the liberalization of and increase in international travel and trade, an economic phenomenon. Second, the costs of invasions are rising rapidly due partly to increasing human population density, and partly to increasing intensity of production in genetically impoverished agricultural systems. Third, biological invasions are associated with a high degree of uncertainty both because they involve novel interactions, and because invasion risks are endogenous. Actual risks depend on how people react to the possibility of invasions. Fourth, the exclusion and control of invasive species is a "weakest-link" public good. This places the well-being of society in the hands of the least effective provider. We argue that an economic solution to the problem of invasive species has two components. One is to use incentives to change human behavior so as to enhance protection against the introduction, establishment, and spread of invasive behavior. The other is to develop institutions that support the weakest members of global society, converting a "weakest-link" to a "best-shot" public good.

User authentication through keystroke dynamics

Abstract: Unlike other access control systems based on biometric features, keystroke analysis has not led to techniques providing an acceptable level of accuracy. The reason is probably the intrinsic variability of typing dynamics, versus other---very stable---biometric characteristics, such as face or fingerprint patterns. In this paper we present an original measure for keystroke dynamics that limits the instability of this biometric feature. We have tested our approach on 154 individuals, achieving a False Alarm Rate of about 4p and an Impostor Pass Rate of less than 0.01p. This performance is reached using the same sampling text for all the individuals, allowing typing errors, without any specific tailoring of the authentication system with respect to the available set of typing samples and users, and collecting the samples over a 28.8-Kbaud remote modem connection.

The Effect of Child Care and Part Time Opportunities on Participation and Fertility Decisions in Italy

Abstract: Economic models of household behavior typically yield the prediction that increases in schooling levels and wage rates of married women lead to increases in their labor supply and reductions in fertility. In Italy, as well as in other Southern European countries, low labor market participation rates of married women are observed together with low birth rates. Our proposed explanation for this apparent anomaly involves the Italian institutional structure, particularly as reflected in rigidities and imperfections in the labor market and characteristics of the publicly-funded child care system. These rigidities tend to simultaneously increase the costs of having children and to discourage the labor market participation of married women. We analyze a model of labor supply and fertility, using panel data from the Bank of Italy which have been merged with regional data describing the available opportunities in each sample household's environment. The empirical results show that the availability of child care and part time work increase both the probability of working and having a child. Policies which would provide more flexible working hours choices and greater child care availability would aid in reducing the financial burden of children.

Breaking the neuronal sphere: regulation of the actin cytoskeleton in neuritogenesis

Abstract: The sprouting of neurites, which will later become axons and dendrites, is an important event in early neuronal differentiation. Studies in living neurons indicate that neuritogenesis begins immediately after neuronal commitment, with the activation of membrane receptors by extracellular cues. These receptors activate intracellular cascades that trigger changes in the actin cytoskeleton, which promote the initial breakdown of symmetry. Then, through the regulation of gene transcription, and of microtubule and membrane dynamics, the newly formed neurite becomes stabilized. A key challenge is to define the molecular machinery that regulates the actin cytoskeleton during initial neurite sprouting. We propose that analysing the molecules involved in actin-dependent mechanisms in non-neuronal systems, such as budding yeast and migrating fibroblasts, could help to uncover the secrets of neuritogenesis.

Effects of Recruiting Maneuvers in Patients with Acute Respiratory Distress Syndrome Ventilated with Protective Ventilatory Strategy

Abstract: Background: A lung-protective ventilatory strategy with low tidal volume (VT) has been proposed for use in acute respiratory distress syndrome (ARDS). Alveolar derecruitment may occur during the use of a lung-protective ventilatory strategy and may be prevented by recruiting maneuvers. This study examined the hypothesis that the effectiveness of a recruiting maneuver to improve oxygenation in patients with ARDS would be influenced by the elastic properties of the lung and chest wall. Methods: Twenty-two patients with ARDS were studied during use of the ARDSNet lung-protective ventilatory strategy: VT was set at 6 ml/kg predicted body weight and positive end-expiratory pressure (PEEP) and inspiratory oxygen fraction (FIO2) were set to obtain an arterial oxygen saturation of 90 ‐95% and/or an arterial oxygen partial pressure (PaO2 )o f 60 ‐ 80 mmHg (baseline). Measurements of PaO2/FIO2, static volume‐ pressure curve, recruited volume (vertical shift of the volumepressure curve), and chest wall and lung elastance (EstW and EstL: esophageal pressure) were obtained on zero end-expiratory pressure, at baseline, and at 2 and 20 min after application of a recruiting maneuver (40 cm H2O of continuous positive airway pressure for 40 s). Cardiac output (transesophageal Doppler) and mean arterial pressure were measured immediately before, during, and immediately after the recruiting maneuver. Patients were classified a priori as responders and nonresponders on the basis of the occurrence or nonoccurrence of a 50% increase in PaO2/FIO2 after the recruiting maneuver. Results: Recruiting maneuvers increased PaO2/FIO2 by 20 3% in nonresponders (n 11) and by 175 23% (n 11; mean standard deviation) in responders. On zero end-expiratory pressure, EstL (28.4 2.2 vs. 24.2 2.9 cm H2O/l) and EstW (10.4 1.8 vs. 5.6 0.8 cm H2O/l) were higher in nonresponders than in responders (P < 0.01). Nonresponders had been ventilated for a longer period of time than responders (7 1 vs. 1 0.3 days; P < 0.001). Cardiac output and mean arterial pressure decreased by 31 2 and 19 3% in nonresponders and by 2 1 and 2 1% in responders (P < 0.01). Conclusions: Application of recruiting maneuvers improves oxygenation only in patients with early ARDS who do not have impairment of chest wall mechanics and with a large potential for recruitment, as indicated by low values of EstL. TRADITIONAL respiratory support for the acute respiratory distress syndrome (ARDS) involves the use of relatively large (10 –15 ml/kg) tidal volumes (VT) to minimize atelectasis and positive end-expiratory pressure (PEEP) to improve arterial oxygenation by means of low inspiratory oxygen fractions (FIO2). 1 More recently, lungprotective ventilatory strategies have been proposed 2 that are based on the large body of animal data indicating that mechanical ventilation with high VT is associated with pulmonary injury indistinguishable from ARDS. 3 Cycling end-expiratory collapse with tidal inflation may exacerbate this process. 4 Three recent randomized controlled trials supported these experimental findings, showing that a lung-protective ventilatory strategies based on low VT is able to decrease markers of pulmonary and systemic inflammation 5 and decrease mortality among patients with ARDS. 6,7

The Semaphorin 4D receptor controls invasive growth by coupling with Met

Abstract: Semaphorins are cell surface and soluble signals that control axonal guidance1,2. Recently, semaphorin receptors (plexins) have been discovered and shown to be widely expressed3,4,5. Their biological activities outside the nervous system and the signal transduction mechanism(s) they utilize are largely unknown. Here, we show that in epithelial cells, Semaphorin 4D (Sema 4D) triggers invasive growth, a complex programme that includes cell–cell dissociation, anchorage-independent growth and branching morphogenesis6. Interestingly, the same response is also controlled by scatter factors through their tyrosine kinase receptors, which share striking structural homology with plexins in their extracellular domain 3. We found that in cells expressing the endogenous proteins, Plexin B1 (the Sema 4D Receptor) and Met (the Scatter Factor 1/ Hepatocyte Growth Factor Receptor) associate in a complex. In addition, binding of Sema 4D to Plexin B1 stimulates the tyrosine kinase activity of Met, resulting in tyrosine phosphorylation of both receptors. Finally, cells lacking Met expression do not respond to Sema 4D unless exogenous Met is expressed. This work identifies a novel biological function of semaphorins and suggests the involvement of an unexpected signalling mechanism, namely, the coupling of a plexin to a tyrosine kinase receptor.

The endophilin–CIN85–Cbl complex mediates ligand-dependent downregulation of c-Met

Abstract: Ligand-dependent downregulation of tyrosine kinase receptors is a critical step for modulating their activity. Upon ligand binding, hepatocyte growth factor (HGF) receptor (Met) is polyubiquitinated and degraded; however, the mechanisms underlying HGF receptor endocytosis are not yet known. Here we demonstrate that a complex involving endophilins, CIN85 and Cbl controls this process. Endophilins are regulatory components of clathrin-coated vesicle formation. Through their acyl-transferase activity they are thought to modify the membrane phospholipids and induce negative curvature and invagination of the plasma membrane during the early steps of endocytosis. Furthermore, by means of their Src-homology 3 domains, endophilins are able to bind CIN85, a recently identified protein that interacts with the Cbl proto-oncogene. Cbl, in turn, binds and ubiquitinates activated HGF receptor, and by recruiting the endophilin-CIN85 complex, it regulates receptor internalization. Inhibition of complex formation is sufficient to block HGF receptor internalization and to enhance HGF-induced signal transduction and biological responses. These data provide further evidence of a relationship between receptor-mediated signalling and endocytosis, and disclose a novel functional role for Cbl in HGF receptor signalling.

The effect of child care and part time opportunities on participation and fertility decisions in Italy

Abstract: Economic models of household behavior typically yield the prediction that increases in schooling levels and wage rates of married women lead to increases in their labor supply and reductions in fertility. In Italy, low labor market participation rates of married women are observed together with low birth rates. Our explanation involves the Italian institutional structure, particularly as reflected in rigidities and imperfections in the labor market and characteristics of the publicly-funded child care system. These rigidities tend to simultaneously increase the costs of having children and to discourage the labor market participation of married women. We analyze a model of labor supply and fertility, using panel data. The empirical results show that the availability of child care and part time work increase both the probability of working and having a child.

Periodontal plastic surgery for treatment of localized gingival recessions: a systematic review.

Abstract: Background: The evidence for the efficacy of periodontal plastic surgery (PPS) in the treatment of recession defects has not yet been systematically evaluated. The objective of this review was to systematically review the efficacy of PPS in achieving root coverage in the treatment of localized gingival recession. The following surgical procedures have been considered in this review: guided tissue regeneration (GTR), free gingival graft (FGG), connective tissue graft (CTG), and coronally advanced flap (CAF). Methods: Randomized and controlled trials, as well as case series of at least 6 months' follow-up, were searched. Data sources included electronic databases and hand-searched journals. Screening, data abstraction and quality assessment were conducted independently and in duplicate. Results: Regarding recession reduction, a limited but statistically significant greater benefit was found for CTG compared with GTR (weighted mean difference: 0.43 mm, 95% CI: 0.62–0.23). No differences were found comparing either GTR with CAF or resorbable versus non-resorbable GTR barriers. Gain in attachment was also similar for each of the three comparisons. Analysis of single arms of trials and case series demonstrated that PPS can have a marked improvement on clinical parameters but heterogeneity was often high and only partly explained by initial defect depth. Conclusions: Overall, PPS was effective in reducing gingival recessions with a concomitant improvement in attachment levels. Even though no single treatment can be considered superior to all the others, CTG was statistically significantly more effective than GTR in recession reduction. Further research is needed to identify the factors most associated with successful outcomes.

Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas.

Abstract: Two conferences were sponsored by the International Society for Cutaneous Lymphomas (ISCL) to gain consensus on definitions and terminology for clinical use in erythrodermic cutaneous T-cell lymphoma (E-CTCL). Three subsets of E-CTCL were defined: Sezary syndrome ("leukemic phase" E-CTCL), erythrodermic mycosis fungoides (secondary E-CTCL that develops in patients with mycosis fungoides), and E-CTCL, not otherwise defined. The hematologic criteria recommended for Sezary syndrome are intended to identify patients with a worse prognosis compared with the other E-CTCL subsets and consist of one or more of the following: (1) an absolute Sezary cell count of 1000 cells/mm3 or more; (2) a CD4/CD8 ratio of 10 or higher caused by an increase in circulating T cells and/or an aberrant loss or expression of pan-T cell markers by flow cytometry; (3) increased lymphocyte counts with evidence of a T-cell clone in the blood by the Southern blot or polymerase chain reaction technique; or (4) a chromosomally abnormal T-cell clone. For staging purposes, it is proposed that these criteria define the B2 blood rating and that the B2 rating be considered equivalent to nodal involvement.

Multipotent Neural Stem Cells Reside into the Rostral Extension and Olfactory Bulb of Adult Rodents

Abstract: The lateral walls of the forebrain lateral ventricles are the richest source of stem cells in the adult mammalian brain. These stem cells give rise to new olfactory neurons that are renewed throughout life. The neurons originate in the subventricular zone (SVZ), migrate within the rostral extension (RE) of the SVZ along the rostral migratory stream (RMS) within tube-like structures formed of glial cells, to eventually reach the olfactory bulb (OB). We demonstrate that, contrary to the current view, multipotential (neuronal-astroglial-oligodendroglial) precursors with stem cell features can be isolated not only from the SVZ but also from the entire RE, including the distal portion within the OB. Specifically, these stem cells do not derive from the migratory neuroblasts coming from the SVZ. Interestingly, stem cells isolated from the proximal RE generate significantly more oligodendrocytes, and those from the distal RE proliferate significantly more slowly than stem cells derived from the SVZ and other RE regions. These findings demonstrate that stem cells are not confined to the forebrain periventricular region and indicate that stem cells endowed with different functional characteristics occur at different levels of the SVZ-RE pathway.

Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death

Abstract: The anaplastic lymphoma kinase (ALK) gene is characteristically translocated in Anaplastic Large Cell Lymphomas (ALCL) and the juxtaposition of the ALK gene to multiple partners results in its constitutive protein tyrosine kinase activity. We show here that expression of activated ALK induces the constitutive phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs. Furthermore, immunohistochemical studies demonstrate that among distinct human B and T cell lymphomas, activation of Stat3 nuclear translocation is uniquely associated with ALK expression. NPM-ALK also binds and activates Jak3; however, Jak3 is not required for Stat3 activation or for cell transformation in vitro. Moreover, src family kinases are not necessary for NPM-ALK-mediated Stat3 activation or transformation, suggesting that Stat3 may be phosphorylated directly by ALK. To evaluate relevant targets of ALK-activated Stat3, we investigated the regulation of the anti-apoptotic protein Bcl-x(L) and its role in cell survival in NPM-ALK positive cells. NPM-ALK expression caused enhanced Bcl-x(L) transcription, largely mediated by Stat3. Increased expression of Bcl-x(L) provided sufficient anti-apoptotic signals to protect cells from treatment with specific inhibitors of the Jaks/Stat pathway or the Brc-Abl kinase. These studies support a pathogenic mechanism whereby stimulation of anti-apoptotic signals through activation of Stat3 contributes to the successful outgrowth of ALK positive tumor cells.

Paramagnetic lanthanide(III) complexes as pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications.

Abstract: The recently introduced new class of contrast agents (CAs) based on chemical exchange saturation transfer (CEST) may have a huge potential for the development of novel applications in the field of MRI. In this work we explored the CEST properties of a series of Lanthanide(III) complexes (Ln = Eu, Dy, Ho, Er, Tm, Yb) with the macrocyclic DOTAM-Gly ligand, which is the tetraglycineamide derivative of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). These complexes possess two pools of exchangeable protons represented by the coordinated water and the amide protons. Yb-DOTAM-Gly displays the most interesting CEST properties when its amide N-H resonance (16 ppm upfield H2O signal) is irradiated. Up to 70% suppression of the water signal is obtained at pH 8. As the exchange rate of amide protons is base-catalyzed, Yb-DOTAM-Gly results to be an efficient pH-responsive probe in the 5.5-8.1 pH range. Moreover, a ratiometric method has been set up in order to remove the dependence of the observed pH responsiveness from the absolute concentration of the paramagnetic agent. In fact, the use of a mixture of Eu-DOTAM-Gly and Yb-DOTAM-Gly, whose exchangeable proton pools are represented by the coordinated water (ca. 40 ppm downfield H2O signal at 312K) and amide protons, respectively, produces a pH-dependent CEST effect which is the function of the concentration ratio of the two complexes.

Hemopexin: Structure, Function, and Regulation

Abstract: Hemopexin (HPX) is the plasma protein with the highest binding affinity to heme among known proteins. It is mainly expressed in liver, and belongs to acute phase reactants, the synthesis of which is induced after inflammation. Heme is potentially highly toxic because of its ability to intercalate into lipid membrane and to produce hydroxyl radicals. The binding strength between heme and HPX, and the presence of a specific heme–HPX receptor able to catabolize the complex and to induce intracellular antioxidant activities, suggest that hemopexin is the major vehicle for the transportation of heme in the plasma, thus preventing heme-mediated oxidative stress and heme-bound iron loss. In this review, we discuss the experimental data that support this view and show that the most important physiological role of HPX is to act as an antioxidant after blood heme overload, rather than to participate in iron metabolism. Particular attention is also put on the structure of the protein and on its regulation during the...

Expression of Ghrelin and of the GH Secretagogue Receptor by Pancreatic Islet Cells and Related Endocrine Tumors

Abstract: Ghrelin is a novel gastrointestinal hormone produced by rat and human gastric X-like neuroendocrine cells, which strongly stimulates GH secretion and influences energy balance, gastric motility, and acid secretion. Ghrelin is expressed in pituitary and gastrointestinal endocrine tumors. It binds to the GH secretagogue receptor (GHS-R), which is present in a wide variety of central and peripheral human tissues. The aim of the present study was 2-fold: 1) to determine, by immunohistochemistry and mRNA analysis, whether pancreatic islet cells produce ghrelin and express GHS-R; and 2) to investigate ghrelin and GHS-R expression in pancreatic endocrine tumors. Seven cases of nonneoplastic pancreatic tissue and 28 endocrine tumors were studied. In pancreatic islets, ghrelin immunoreactivity was present in all cases and confined to beta-cells. Eleven of the 28 (39%) endocrine tumors were immunoreactive for ghrelin. In situ hybridization and RT-PCR confirmed the immunohistochemical data for both tumors and islets but also revealed ghrelin mRNA in 8 and 11 additional tumors, respectively. GHS-R 1a and 1b mRNAs were present in 7 of 28 and 14 of 28 tumors, respectively, studied by RT-PCR. These findings demonstrate that ghrelin production is not restricted to the stomach but is also present in pancreatic beta-cells and endocrine tumors (regardless of the type of pancreatic hormone produced, if any). Expression of GHS-R in some of the endocrine tumors studied indicates that autocrine/paracrine circuits may be active in neoplastic conditions.