La pena di morte: una pena giuridica?

Il lavoro di tesi si propone di affrontare il dibattito, sempre attuale e mai esaurito, su la pena di morte con tutte le implicazioni storiche, etiche, giuridiche, filosofiche e sociologiche che la giustificano

Opioid metabolism and drug-drug interaction in cancer

Concomitant use of multiple drugs in most patients with cancer may result in drug-drug interactions (DDIs), potentially causing serious adverse effects. These patients often experience unrelieved cancer-related pain (CRP) during and after cancer treatment, which can lead to a reduced quality of life. Opioids can be used as part of a multimodal pain management strategy when non-opioid analgesics are not providing adequate pain relief, not tolerated, or are contraindicated. However, due to their narrow therapeutic window, opioids are more susceptible to adverse events when a DDI occurs. Clinically relevant DDIs with opioids are usually pharmacokinetic, mainly occurring via metabolism by cytochrome P450 (CYP). This article aims to provide an overview of potential DDIs with opioids often used in the treatment of moderate-to-severe CRP and commonly used anticancer drugs such as chemotherapeutics, tyrosine kinase inhibitors (TKIs), or biologics. A DDI-checker tool was used to contextualize the tool-informed DDI assessment outcomes with clinical implications and practice. The findings were compared to observations from a literature search conducted in Embase and PubMed to identify clinical evidence for these potential DDIs. The limited results mainly included case studies and retrospective reviews. Some potential DDIs on the DDI-checker were aligned with literature findings, while others were contradictory. In conclusion, while DDI-checkers are useful tools in identifying potential DDIs, it is necessary to incorporate literature verification and comprehensive clinical assessment of the patient before implementing tool-informed decisions in clinical practice

Circulating MicroRNAs in Cutaneous Melanoma Diagnosis and Prognosis

Cutaneous melanoma represents a challenge for pharmacologists and clinicians due to their high degree of genetic and phenotypic heterogeneity. The identification of new non-invasive and informative biomarkers would therefore represent a substantial step to adequately treat melanoma patients. MicroRNAs (miRNAs) are a class of small non-coding RNAs that play an important role as negative regulators of gene expression. Several studies have demonstrated their correlation with disease status in different types of cancer including melanoma. Extracellular miRNAs are released from both tumor cells and/or normal cells. MiRNAs do not circulate freely in biological fluids but they are incorporated into extracellular vesicles or form complexes with lipids and proteins. Circulating miRNAs may represent potential biomarkers of cutaneous melanoma diagnosis and patient prognosis. Longitudinal monitoring of cell-free miRNAs in biological fluids of melanoma patients could help clinicians to predict disease progression before the tumor becomes resistant to a given drug. However, to confirm their clinical utility it will be necessary to validate the best available technique for their detection and quantification and to test selected miRNAs in prospective clinical trials

Full vectorial BPM modeling of Index-Guiding Photonic Crystal Fibers and Couplers

A 3D full-vectorial Beam Propagation Method is successfully applied to compute both the propagation constants and the modal profiles in high-contrast silica-air index-guiding Photonic Crystal Fibers. The approach is intrinsically suited to investigate longitudinally varying structures or propagation and polarization effects, which are of practical interest for advanced optical applications. As an example we model a dual-core coupler, showing that efficient polarization preserving coupling can be expected

Gemcitabine, epirubicin and paclitaxel: pharmacokinetic and pharmacodynamic interactions in advanced breast cancer

BACKGROUND: The objectives of this study were to investigate the disposition of gemcitabine, epirubicin, paclitaxel, 2',2'-difluorodeoxyuridine and epirubicinol, and characterize the pharmacokinetic and pharmacodynamic profile of treatment in patients with breast cancer. PATIENTS AND METHODS: The drug dispostion in 15 patients who received gemcitabine 1000 mg/m2, epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (GEP) on day 1 of a 21-day cycle, was compared with that of patients treated with epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (EP, n = 6) and epirubicin 90 mg/m2 alone (n = 6). Drug and metabolite levels in plasma and urine were assessed by high-performance liquid chromatography and parameters of drug exposure were related to hematological toxicity by a sigmoid-maximum effect (Emax) model. RESULTS: Paclitaxel administration significantly increased the epirubicinol area under the concentration-time curve, from 357+/-146 (epirubicin) to 603+/-107 (EP) and 640+/-81 h x ng/ml (GEP), and reduced the renal clearance of epirubicin and epirubicinol by 38 and 52.2% and 34.5 and 53% in GEP- and EP-treated patients, respectively, compared with epirubicin alone. Gemcitabine had no apparent effect on paclitaxel and epirubicin pharmacokinetics, and renal clearance of epirubicin and epirubicinol. The only pharmacokinetic/pharmacodynamic relationship observed was between neutropenia and the time spent above the threshold plasma level of 0.1 micromol/l (tC0.1) of paclitaxel, with the time required to obtain a 50% decrease in neutrophil count (Et50) of GEP being 7.8 h, similar to that of EP. CONCLUSIONS: Paclitaxel and/or its vehicle, Cremophor EL, interferes with the disposition and renal excretion of epirubicin and epirubicinol; gemcitabine has no affect on epirubicin and paclitaxel plasma pharmacokinetics and renal excretion of epirubicin, while neutropenia is not enhanced by gemcitabine

Cholinesterase-like organocatalysis by imidazole and imidazole-bearing molecules

Organocatalysis, which is mostly explored for its new potential industrial applications, also represents a chemical event involved in endogenous processes. In the present study, we provide the first evidence that imidazole and imidazole derivatives have cholinesterase-like properties since they can accelerate the hydrolysis of acetylthiocholine and propionylthiocholine in a concentration-dependent manner. The natural imidazole-containing molecules as L-histidine and histamine show a catalytic activity, comparable to that of imidazole itself, whereas synthetic molecules, as cimetidine and clonidine, were less active. In the experimental conditions used, the reaction progress curves were sigmoidal and the rational of such unexpected behavior as well as the mechanism of catalysis is discussed. Although indirectly, findings of the present study suggests that imidazolic compounds may interfere with the homeostasis of the cholinergic system in vivo

Implications of KRAS mutations in acquired resistance to treatment in NSCLC

Rationale: KRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies. The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in NSCLC patients. Materials and Methods: A bibliographic search of the Medline database was conducted for articles published in English, with the keywords KRAS, KRAS mutations in non-small cell lung cancer, KRAS and tumorigenesis, KRAS and TKIs, KRAS and chemotherapy, KRAS and monoclonal antibody, KRAS and immunotherapy, KRAS and drugs, KRAS and drug resistance

Oleocanthal and oleacein contribute to the in vitro therapeutic potential of extra virgin oil-derived extracts in non-melanoma skin cancer

Although the anticancer properties of extra virgin olive oil (EVOO) extracts have been recognized, the role of single compounds in non-melanoma skin cancer is still unknown. The in vitro chemopreventive and anticancer action of EVOO extracts and oil-derived compounds in non-melanoma skin cancer models were evaluated on cutaneous squamous cell carcinoma cells and on immortalized human keratinocytes stimulated with epidermal growth factor. Preparation of EVOO extracts and isolation of single compounds was carried out by chromatographic methods. Antitumor activity was assessed by cell-based assays (cell viability, migration, clonogenicity, and spheroid formation) and apoptosis documented by internucleosomal DNA fragmentation. Finally, inhibition of key oncogenic signaling nodes involved in the progression from actinic keratosis to cutaneous squamous cell carcinoma was studied by western blot. EVOO extracts reduced non-melanoma skin cancer cell viability and migration, prevented colony and spheroid formation, and inhibited proliferation of atypical keratinocytes stimulated with epidermal growth factor. Such a pharmacological activity was promoted by oleocanthal and oleacein through the inhibition of Erk and Akt phosphorylation and the suppression of B-Raf expression, whereas tyrosol and hydroxytyrosol did not have effect. The current study provides in vitro evidence for new potential clinical applications of EVOO extracts and/or single oil-derived compounds in the prevention and treatment of non-melanoma skin cancers

Phenomenological Consequences of See-Saw in S4 Based Models

It was proposed a flavour model based on the symmetry group S4, managing to describe fermion masses and mixings. The Weinberg operator has been used in order to provide the smallness of the neutrino masses, while a set of scalar fields, getting non-vanishing vacuum expectation values, spontaneously breaks down S4 and provides the Tri-Bimaximal pattern as the lepton mixing matrix. Restricting to this setting, in this paper we analyze possible origins for the effective terms: the type I See-Saw mechanism is the best known approach, but also the type II and III are discussed. The phenomenology related to these models is various and the next future experiments could in principle discriminate among these proposals. Furthermore, we compare our realizations to two relevant A4 based models, also predicting the Tri-Bimaximal lepton mixing, and we find that an analysis on the neutrinoless double beta decay parameters could distinguish among all these realizations. Furthermore a combined measurement of the effective mass and of the lightest neutrino mass could indicate in the next future which is the preferred flavour symmetry group. The introduction of new physics beyond the Standard Model, like heavy right-handed neutrinos, scalar triplets and fermion triplets, let us investigate on leptogenesis and this provides constraints in the realization of the models.Comment: 32 pages, 14 figures; added references and minor correctio

Fermion Masses and Mixings in a S4 Based Model

It has been recently claimed that the symmetry group S4 yields to the Tri-bimaximal neutrino mixing in a "natural" way from the group theory point of view. Approving of this feature as an indication, we build a supersymmetric model of lepton and quark masses based on this family symmetry group. In the lepton sector, a correct mass hierarchy among the charged leptons is achieved together to a neutrino mass matrix which can be diagonalized by the Tri-bimaximal pattern. Our model results to be phenomenologically unequivalent with respect to other proposals based on different flavour groups but still predicting the Tri-bimaximal mixing. In the quark sector a realistic pattern for masses and mixing angles is obtained. The flavour structures of the mass matrices in both the sectors come from the spontaneously symmetry breaking of S4, due to several scalar fields, which get non-zero vacuum expectation values. A specific vacuum alignment is required and it is shown to be a natural results of the minimization of the scalar potential and, moreover, to be stable under the corrections from the higher order terms.Comment: 25 pages, LaTeX; added references and minor correctio