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Cesario A.,IRCCS San Raffaele Pisana | Rocca B.,Catholic University Med School | Rutella S.,IRCCS San Raffaele Pisana | Rutella S.,Catholic University Med School
Current Medicinal Chemistry | Year: 2011

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrades the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favor the differentiation of regulatory T cells. IDO1 is traditionally viewed as a general suppressor of T-cell activation and mediator of immune escape in cancer. Recently, evidence has emerged to support a greater functional complexity of IDO1 as modifier of pathogenic inflammation. For instance, IDO1 activity may sustain autoantibody production by B cells, and elicit the development of cancer in the context of chronic inflammation. Cyclooxygenase (COX)-2 metabolizes the first enzymatic step in the conversion of arachidonic acid into prostanoids. In particular, prostaglandin (PG)E2 generated at sites of inflammation and/or immune response is mainly COX-2-derived and has pro-inflammatory and immune regulatory activities. Pharmacological blockade of COX-2 in animal models of cancer translates into down-regulation of IDO1 expression at tumor sites and decreased levels of kynurenine in the circulation, underpinning the view that IDO1 might be downstream of COX-2. This article reviews preclinical studies focusing on IDO1 and COX-2 as inter-related molecular targets for therapeutic intervention in chronic inflammation and cancer. COX-2 inhibition might, in principle, be pursued in cancer-associated inflammation characterized by IDO1 hyper-activity, with the foreseeable aim at altering the immune response within the tumor microenvironment. © 2011 Bentham Science Publishers Ltd.


Ferroni P.,IRCCS San Raffaele Pisana | Riondino S.,IRCCS San Raffaele Pisana | Vazzana N.,University of Chieti Pescara | Santoro N.,University of Chieti Pescara | And 2 more authors.
Thrombosis and Haemostasis | Year: 2012

The most convincing evidence for the participation of platelets in arterial thrombosis in humans comes from studies of platelet activation in patients with acute coronary syndromes (ACS) and from trials of anti-platelet drugs. Both strongly support the concept that repeated episodes of platelet activation over the thrombogenic surface of a vulnerable plaque may contribute to the risk of death from coronary causes. However, the relation of in vivo platelet activation and adverse clinical events to results of platelet function tests remains largely unknown. A valuable marker of in vivo platelet activation should be specific, unal-tered by pre-analytical artefacts and reproducibly measured by easily performed methods. This article describes current biomarkers of platelet activation in ACS, reviews their advantages and disadvantages, discusses their potential pitfalls, and demonstrates emerging data supporting the positive clinical implications of monitoring in vivo platelet activation in the setting of ACS. © Schattauer 2012.


Shewan L.G.,Monash University | Shewan L.G.,University of Warwick | Rosano G.,IRCCS San Raffaele Pisana | Henein M.,Umeå University | And 2 more authors.
International Journal of Cardiology | Year: 2014

All authors of manuscripts in the International Journal of Cardiology family of journals: The International Journal of Cardiology, IJC Heart & Vessels and IJC Metabolic & Endocrine are required to make a binding statement that they as authors adhere to the following principles:That the corresponding author has the approval of all other listed authors for the submission and publication of all versions of the manuscript, that all authors have made a significant independent contribution and that no one who justifies being an author has been omitted from authorshipThat the work has not been published nor is under consideration for publication elsewhere other than in oral, poster or abstract format, and that appropriate attribution and citation is given for any material reproduced from any other source including the authors' prior publicationsThat the material in the manuscript has been acquired according to modern ethical standards and has been approved by the legally appropriate ethical committee(s)That all material conflicts of interest have been declared including the use of paid medical writers and their funding source.That the manuscript will be maintained on the servers of the journals and held to be a valid publication by the journals only as long as all statements in these principles remain true, and that the authors have a duty to notify the journal editors immediately if any of the statements above ceases to be true withdrawn. © 2013 Elsevier Ireland Ltd.


Sale P.,IRCCS San Raffaele Pisana | Franceschini M.,IRCCS San Raffaele Pisana | Waldner A.,Privatklinik Villa Melitta | Hesse S.,Charité - Medical University of Berlin
European Journal of Physical and Rehabilitation Medicine | Year: 2012

Difficulty in walking is a major feature of neurological disease, and loss of mobility is the activity of daily living on which patients place the greatest value. The impact on patients is enormous, with negative ramifications on their participation in social, vocational, and recreational activities. In current clinical practice the gait restoration with robotic device is an integral part of rehabilitation program. Robot therapy involves the use of a robot exoskeleton device or end-effector device to help the patient retrain motor coordination by performing well-focused and carefully directed repetitive practice. The exoskeleton, as an assistive device, is also an external structural mechanism with joints and links corresponding to those of the human body. These robots use joint trajectories of the entire gait cycle and offer a uniform (more or less) stiff control along this trajectory. In this field the new powered exoskeleton ReWalk (Argo Medical Technologies Ltd) was developed to have an alternative mobility solution to the wheelchair and rehabilitation treatment for individuals with severe walking impairments, enabling them to stand, walk, ascend/descent stairs and more. The end-effector-based robot is a device with footplates placed on a double crank and rocker gear system. Alternatives to powered exoskeletons are devices that use movable footplates to which the patient's feet are attached. All devices include some form of body weight support. Prominent goals in the field include: developing implementable technologies that can be easily used by patients, therapists, and clinicians; enhancing the efficacy of clinician's therapies and increasing the ease of activities in the daily lives of patients.


Stocchi F.,IRCCS San Raffaele Pisana | Olanow C.W.,IRCCS San Raffaele Pisana | Olanow C.W.,Mount Sinai School of Medicine
Movement Disorders | Year: 2013

A neuroprotective or disease-modifying therapy that can slow or stop disease progression and prevent the development of intolerable disability is the major unmet medical need in the treatment of Parkinson's disease (PD). Many putative neuroprotective agents have been identified in the laboratory, but none has been unequivocally demonstrated to provide disease-modifying effects in PD patients, even when clinical trials are positive. Obstacles to defining a neuroprotective therapy in PD include: (1) uncertainty about the cause of PD and precisely what to target, (2) a reliable animal model in which to test putative neuroprotective agents that accurately predicts results in PD patients, (3) insight about which dose to employ in clinical trials and which patient group to study, (4) a clinical trial design that reliably differentiates disease-modifying and symptomatic effects and that is acceptable to regulatory authorities, and (5) the cost and time of the development program. Advances have been made in each of these areas, thereby increasing the prospects of developing a neuroprotective or disease-modifying therapy in the not-too-distant future. These issues are reviewed in the present article. © 2013 Movement Disorder Society.


Russo P.,IRCCS San Raffaele Pisana | Nastrucci C.,IRCCS San Raffaele Pisana | Cesario A.,IRCCS San Raffaele Pisana | Cesario A.,Catholic University
Current Medicinal Chemistry | Year: 2011

Discovery, isolation, characterisation and pre-clinical and clinical trials of plant- or animal-derived drugs displaying pharmacological activities continue to develop and enlarge. Cancer chemotherapy is one of the most promising areas for these drugs. Since a very long time, nature has been an attractive source of potential medicinal agents for human use. The deep sea is becoming a novel and potently appealing source for new drugs, as well as shallow waters. This interest is mainly related to the terrific chemical diversity found in the vast number of plants and animal species, as well as in the microbial world. During the evolution, a rich source of biologically active compounds is developed in the depths of the sea, often reflecting ecological adaptation. Most of them (toxins) are developed to allow survival and flourishing acting against predators and parasites. Recent progress in Scuba diving, hitech/biotechnological and procedural advances in structure clarification, organic synthesis and biological assay determined the characterisation and preclinical/clinical evaluation of novel anticancer drugs. The aim of this review is to provide a description of their discovery, mode of action and clinical application.


Sale P.,IRCCS San Raffaele Pisana | Lombardi V.,IRCCS San Raffaele Pisana | Franceschini M.,IRCCS San Raffaele Pisana
Stroke Research and Treatment | Year: 2012

Background. No strongly clinical evidence about the use of hand robot-assisted therapy in stroke patients was demonstrated. This preliminary observer study was aimed at evaluating the efficacy of intensive robot-assisted therapy in hand function recovery, in the early phase after a stroke onset. Methods. Seven acute ischemic stroke patients at their first-ever stroke were enrolled. Treatment was performed using Amadeo robotic system (Tyromotion GmbH Graz, Austria). Each participant received, in addition to inpatients standard rehabilitative treatment, 20 sessions of robotic treatment for 4 consecutive weeks (5 days/week). Each session lasted for 40 minutes. The exercises were carried out as follows: passive modality (5 minutes), passive/plus modality (5 minutes), assisted therapy (10 minutes), and balloon (10 minutes). The following impairment and functional evaluations, Fugl-Meyer Scale (FM), Medical Research Council Scale for Muscle Strength (hand flexor and extensor muscles) (MRC), Motricity Index (MI), and modified Ashworth Scale for wrist and hand muscles (AS), were performed at the beginning (T0), after 10 sessions (T1), and at the end of the treatment (T2). The strength hand flexion and extension performed by Robot were assessed at T0 and T2. The Barthel Index and COMP (performance and satisfaction subscale) were assessed at T0 and T2. Results. Clinical improvements were found in all patients. No dropouts were recorded during the treatment and all subjects fulfilled the protocol. Evidence of a significant improvement was demonstrated by the Friedman test for the MRC (P<0.0123). Evidence of an improvement was demonstrated for AS, FM, and MI. Conclusions. This original rehabilitation treatment could contribute to increase the hand motor recovery in acute stroke patients. The simplicity of the treatment, the lack of side effects, and the first positive results in acute stroke patients support the recommendations to extend the clinical trial of this treatment, in association with physiotherapy and/or occupational therapy. © 2012 Patrizio Sale et al.


Sale P.,IRCCS San Raffaele Pisana | Franceschini M.,IRCCS San Raffaele Pisana
European Journal of Physical and Rehabilitation Medicine | Year: 2012

Mirror neurons are a specific class of neurons that are activated and discharge both during observation of the same or similar motor act performed by another individual and during the execution of a motor act. Different studies based on non invasive neuroelectrophysiological assessment or functional brain imaging techniques have demonstrated the presence of the mirror neuron and their mechanism in humans. Various authors have demonstrated that in the human these networks are activated when individuals learn motor actions via execution (as in traditional motor learning), imitation, observation (as in observational learning) and motor imagery. Activation of these brain areas (inferior parietal lobe and the ventral premotor cortex, as well as the caudal part of the inferior frontal gyrus [IFG]) following observation or motor imagery may thereby facilitate subsequent movement execution by directly matching the observed or imagined action to the internal simulation of that action. It is therefore believed that this multi-sensory actionobservation system enables individuals to (re) learn impaired motor functions through the activation of these internal action-related representations. In humans, the mirror mechanism is also located in various brain segment: in Broca's area, which is involved in language processing and speech production and not only in centres that mediate voluntary movement, but also in cortical areas that mediate visceromotor emotion-related behaviours. On basis of this finding, during the last 10 years various studies were carry out regarding the clinical use of action observation for motor rehabilitation of sub-acute and chronic stroke patients.


Cardinale A.,IRCCS San Raffaele Pisana | Biocca S.,University of Rome Tor Vergata
International Journal of Cell Biology | Year: 2013

Prion diseases or transmissible spongiform encephalopathies (TSE) are a group of neurodegenerative and infectious disorders characterized by the conversion of a normal cellular protein PrPC into a pathological abnormally folded form, termed PrPSc. There are neither available therapies nor diagnostic tools for an early identification of individuals affected by these diseases. New gene-based antibody strategies are emerging as valuable therapeutic tools. Among these, intrabodies are chimeric molecules composed by recombinant antibody fragments fused to intracellular trafficking sequences, aimed at inhibiting, in vivo, the function of specific therapeutic targets. The advantage of intrabodies is that they can be selected against a precise epitope of target proteins, including protein-protein interaction sites and cytotoxic conformers (i.e., oligomeric and fibrillar assemblies). Herein, we address and discuss in vitro and in vivo applications of intrabodies in prion diseases, focussing on their therapeutic potential. © 2013 Alessio Cardinale and Silvia Biocca.


Only 50% of hypertensive patients receive an appropriate treatment to normalize blood pressure (BP). Although monotherapy is often adequate in normalizing BP, it is sometimes necessary to start with combination therapy. The aim of the study was to evaluate the efficacy of nebivolol alone and in association with hydrochlorothiazide (HCT) in reducing BP in hypertensive patients with new-onset, mild-to-moderate hypertension, and to assess the effect of combination therapy on glucose and lipid metabolism. At enrollment, patients underwent a full cardiovascular and metabolic evaluation. Patients were then prescribed nebivolol (5 mg/day). After 1 month, in those patients whose BP was not normalized, HCT 12.5 mg was added and increased further to 25 mg after 1 month in those whose BP still was not normalized. All patients were assessed at monthly intervals for a further 5 months. We enrolled 233 treatment-naive patients. After the first month of treatment with nebivolol, 70% of patients had normalized BP. The addition of HCT increased responder rates to 94%. An improvement in glucose metabolism was noted with nebivolol alone (at 1 month, the reduction in Homeostasis Model Assessment of Insulin Resistance [HOMA-IR] was 26% and remained stable at 6 months); the adjunct of HCT blunted the reduction in HOMA-IR. No significant changes on lipid profile were noted with nebivolol, either alone or in combination therapy. Nebivolol is effective in mild-to-moderate hypertension and associated with favorable metabolic effects. The addition of HCT optimizes BP control in a high number of patients resistant to monotherapy without a negative impact on patients' glucose and lipid profile.

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