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Patrignani P.,University of Chieti Pescara | Patrono C.,University Cattolica Del ore
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2015

Acetylsalicylic acid (aspirin) is a prototypic cyclooxygenase (COX) inhibitor. It was synthesized serendipitously from a natural compound, i.e., salicylic acid, with known analgesic activity. This chemical modification, obtained for the first time in an industrial environment in 1897, endowed aspirin with the unique capacity of acetylating and inactivating permanently COX-isozymes. Traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) were developed to mimic the pharmacological effects of aspirin, using aspirin-sensitive experimental models of pain and inflammation as the template for screening new chemical entities. Among the tNSAIDs, some were endowed with moderate COX- selectivity (e.g., diclofenac), but no studies of sufficient size and duration were performed to show any clinically relevant difference between different members of the class. Similarly, no serious attempts were made to unravel the mechanisms involved in the shared therapeutic and toxic effects of tNSAIDs until the discovery of COX-2. This led to characterizing their main therapeutic effects as being COX-2-dependent and their gastrointestinal (GI) toxicity as being COX-1-dependent, and provided a rationale for developing a new class of selective COX-2 inhibitors, the coxibs. This review will discuss the clinical pharmacology of tNSAIDs and coxibs, and the clinical read-outs of COX-isozyme inhibition. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance." © 2014 Elsevier B.V. All rights reserved.

Ricci R.,University Cattolica Del ore
Hereditary Cancer in Clinical Practice | Year: 2016

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract. They feature heterogeneous triggering mechanisms, implying relevant clinical differences. The vast majority of GISTs are sporadic tumors. Rarely, however, GIST-prone syndromes occur, mostly depending on heritable GIST predisposing molecular defects involving the entire organism. These conditions need to be properly identified in order to plan appropriate diagnostic, prognostic and therapeutic procedures. Clinically, GIST-prone syndromes must be thought of whenever GISTs are multiple and/or associated with accompanying signs peculiar to the background tumorigenic trigger, either in single individuals or in kindreds. Moreover, syndromic GISTs, individually considered, tend to show distinctive features depending on the underlying condition. When applicable, genotyping is usually confirmatory. In GIST-prone conditions, the prognostic features of each GIST, defined according to the criteria routinely applied to sporadic GISTs, combine with the characters proper to the background syndromes, defining peculiar clinical settings which challenge physicians to undertake complex decisions. The latter concern preventive therapy and single tumor therapy, implying possible surgical and molecularly targeted options. In the absence of specific comprehensive guidelines, this review will highlight the traits characteristic of GIST-predisposing syndromes, with particular emphasis on diagnostic, prognostic and therapeutic implications, which can help the clinical management of these rare diseases. © 2016 The Author(s).

Mikulska M.,University of Genoa | Calandra T.,University of Lausanne | Sanguinetti M.,University Cattolica Del ore | Poulain D.,French Institute of Health and Medical Research | Viscoli C.,University of Genoa
Critical Care | Year: 2010

Introduction: Timely diagnosis of invasive candidiasis (IC) remains difficult as the clinical presentation is not specific and blood cultures lack sensitivity and need a long incubation time. Thus, non-culture-based methods for diagnosing IC have been developed. Mannan antigen (Mn) and anti-mannan antibodies (A-Mn) are present in patients with IC. On behalf of the Third European Conference on Infections in Leukemia, the performance of these tests was analysed and reviewed.Methods: The literature was searched for studies using the commercially available sandwich enzyme-linked immunosorbent assays (Platelia™, Bio-Rad Laboratories, Marnes-la-Coquette, France) for detecting Mn and A-Mn in serum. The target condition of this review was IC defined according to 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Sensitivity, specificity and diagnostic odds ratios (DOR) were calculated for Mn, A-Mn and combined Mn/A-Mn testing.Results: Overall, 14 studies that comprised 453 patients and 767 controls were reviewed. The patient populations included in the studies were mainly haematological and cancer cases in seven studies and mainly intensive care unit and surgery cases in the other seven studies. All studies but one were retrospective in design. Mn sensitivity was 58% (95% confidence interval [CI], 53-62); specificity, 93% (95% CI, 91-94) and DOR, 18 (95% CI 12-28). A-Mn sensitivity was 59% (95% CI, 54-65); specificity, 83% (95% CI, 79-97) and DOR, 12 (95% CI 7-21). Combined Mn/A-Mn sensitivity was 83% (95% CI, 79-87); specificity, 86% (95% CI, 82-90) and DOR, 58 (95% CI 27-122). Significant heterogeneity of the studies was detected. The sensitivity of both Mn and A-Mn varied for different Candida species, and it was the highest for C. albicans, followed by C. glabrata and C. tropicalis. In 73% of 45 patients with candidemia, at least one of the serological tests was positive before the culture results, with mean time advantage being 6 days for Mn and 7 days for A-Mn. In 21 patients with hepatosplenic IC, 18 (86%) had Mn or A-Mn positive test results at a median of 16 days before radiological detection of liver or spleen lesions.Conclusions: Mn and A-Mn are useful for diagnosis of IC. The performance of combined Mn/A-Mn testing is superior to either Mn or A-Mn testing. © 2010 Mikulska et al.; licensee BioMed Central Ltd.

Capoluongo E.,University Cattolica Del ore
Neurobiology of aging | Year: 2012

Two major susceptibility genes, complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2), have been implicated in age-related macular degeneration (AMD) pathogenesis. We analyzed the association between CFH rs1061170 and/or ARMS2 rs10490924 polymorphisms with central retinal function properties, as evaluated by focal electroretinogram (fERG). Forty early AMD patients, with preserved visual acuity and typical macular lesions, underwent fERG recording (in response to 41 Hz flicker stimuli presented to the central 18 degrees) and CFH/ARMS2 genotyping. Mean fERG amplitude and sensitivity decreased in patients carrying CFH rs1061170 polymorphism (p < 0.01), compared with wild type ones, although visual acuity and funduscopic features were similar across the 2 groups. No significant fERG phase changes were observed. No association was detected between ARMS2 (rs10490924) polymorphism and fERG parameters. Our findings indicate that CFH (rs1061170) polymorphism impacts significantly on retinal function in early AMD patients, and support the hypothesis that dysfunctional CFH might result in early retinal function loss due to a reduction in the immune antioxidant defense mechanism. Copyright © 2012 Elsevier Inc. All rights reserved.

De Luca A.,Malattie Infettive Universitarie | De Luca A.,University Cattolica Del ore | Bianco C.,Malattie Infettive Universitarie | Rossetti B.,Malattie Infettive Universitarie
Current Opinion in Pharmacology | Year: 2014

HCV NS3/4A serine protease inhibitors are the first class of direct acting antivirals (DAA) introduced in clinical practice. The first generation agents, selective against HCV genotype 1, are used in association with pegylated interferons and ribavirin allowing increased cure rates at the price of increased toxicity, significant drug interactions and high risk of selecting mutants conferring cross-resistance to the entire class. A large number of second-wave HCV protease inhibitors are currently in clinical development. Advancements include higher potency, activity against a wider number of genotypes, improved tolerability, easier dosing schedules, although their genetic barrier to resistance remains low, especially for subtype 1a, except for the most recent grazoprevir and ACH-2684. The most relevant progress regards the combination with other classes of DAA allowing construction of interferon-free regimens of short duration, good tolerability with exceptionally high cure rates.

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