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Dietary polyphenols have been widely investigated as antidiabetic agents in cell, animals, human study, and clinical trial. The number of publication (Indexed by Web of Science) on “polyphenols and diabetes” significantly increased since 2010. This review highlights the advances and opportunities of dietary polyphenols as antidiabetic agents. Dietary polyphenols prevent and manage Type 2 diabetes mellitus via the insulin‐dependent approaches, for instance, protection of pancreatic islet β‐cell, reduction of β‐cell apoptosis, promotion of β‐cell proliferation, attenuation of oxidative stress, activation of insulin signaling, and stimulation of pancreas to secrete insulin, as well as the insulin‐independent approaches including inhibition of glucose absorption, inhibition of digestive enzymes, regulation of intestinal microbiota, modification of inflammation response, and inhibition of the formation of advanced glycation end products. Moreover, dietary polyphenols ameliorate diabetic complications, such as vascular dysfunction, nephropathy, retinopathy, neuropathy, cardiomyopathy, coronary diseases, renal failure, and so on. The structure–activity relationship of polyphenols as antidiabetic agents is still not clear. The individual flavonoid or isoflavone has no therapeutic effect on diabetic patients, although the clinical data are very limited. Resveratrol, curcumin, and anthocyanins showed antidiabetic activity in human study. How hyperglycemia influences the bioavailability and bioactivity of dietary polyphenols is not well understood. An understanding of how diabetes alters the bioavailability and bioactivity of dietary polyphenols will lead to an improvement in their benefits and clinical outcomes.

The diffusion of type 2 diabetes (T2D) throughout the world represents one of the most important health problems of this century. Patients suffering from this disease can currently be treated with numerous oral anti-hyperglycaemic drugs, but none is capable of reproducing the physiological action of insulin and, in several cases, they induce severe side effects. Developing new anti-diabetic drugs remains one of the most urgent challenges of the pharmaceutical industry. Multi-target drugs could offer new therapeutic opportunities for the treatment of T2D, and the reported data on type 2 diabetic mice models indicate that these drugs could be more effective and have fewer side effects than mono-target drugs. α-Glucosidases and Protein Tyrosine Phosphatase 1B (PTP1B) are considered important targets for the treatment of T2D: the first digest oligo- and disaccharides in the gut, while the latter regulates the insulin-signaling pathway. With the aim of generating new drugs able to target both enzymes, we synthesized a series of bifunctional compounds bearing both a nitro aromatic group and an iminosugar moiety. The results of tests carried out both in vitro and in a cell-based model, show that these bifunctional compounds maintain activity on both target enzymes and, more importantly, show a good insulin-mimetic activity, increasing phosphorylation levels of Akt in the absence of insulin stimulation. These compounds could be used to develop a new generation of anti-hyperglycemic drugs useful for the treatment of patients affected by T2D.

[Image: see text] Pharmacological chaperones (PCs) are small molecules that bind and stabilize enzymes. They can rescue the enzymatic activity of misfolded or deficient enzymes when they are used at subinhibitory concentration, thus with minimal side effects. Pharmacological Chaperone Therapy (PCT) is an emerging treatment for many lysosomal storage disorders (LSDs) including Gaucher disease, the most common, which is characterized by a deficiency in the GCase enzyme. We report herein a straightforward synthetic strategy to afford C-2 substituted trihydroxypiperidines with different alkyl chains starting from low cost d-mannose. Stereoselective Grignard reagent addition onto a key nitrone intermediate in the presence or absence of a suitable Lewis acid afforded both epimers of the target compounds, after a final reductive amination-ring closure step. We show that the shift of the alkyl chain from the endocyclic nitrogen to the C-2 position leads to a considerable increase in chaperoning efficacy, affording a new compound (4a) able to induce a remarkable 1.9-fold maximal increase in GCase activity.

LMW-PTP has been associated with the development of colorectal cancer (CRC) and with the resistance to chemotherapy in cancer cells. To clarify its role in vivo, we studied LMW-PTP expression in Pirc rats (F344/NTac-Apc am1137 ), genetically prone to CRC and resistant to apoptosis. In the morphologically normal mucosa (NM) of Pirc rats, a dramatic over-expression of LMW-PTP was found compared to wt rats (about 60 times higher). Moreover, LMW-PTP levels further increase in spontaneously developed Pirc colon tumors. To understand if and how LMW-PTP affects resistance to apoptosis, we studied CRC cell lines, sensitive (HT29 and HCT-116), or resistant (HT29R, HCT116R) to 5-Fluorouracil (5-FU): resistant cells over-express LMW-PTP. When resistant cells were challenged with morin, a polyphenol inhibiting LMW-PTP, a fast and dose-related down-regulation of LMW-PTP was observed. 5-FU and morin co-treatment dramatically decreased cell viability, increased apoptosis, and significantly impaired self-renewal ability of all the cancer cell lines we have studied. Similarly, we observed that, in Pirc rats, one-week morin administration (50 mg/kg) down-regulated LMW-PTP and restored the apoptotic response to 5-FU in the NM. Finally, administration of morin for a longer period led to a significant reduction in colon precancerous lesions, together with a down-regulation of LMW-PTP. Taken together, these results document the involvement of LMW-PTP in the process of CRC in vitro and in vivo. Morin treatment may be envisaged as a system to increase the sensitivity to chemotherapy and to prevent carcinogenesis.

A drug delivery system (DDS) for combined therapy, based on a short oxidized multiwalled carbon nanotube, is reported. It was prepared by exploiting a synthetic approach which allowed loading of two drugs, doxorubicin and metformin, the targeting agent biotin and a radiolabeling tag, to enable labeling with Ga-68 or Cu-64 in order to perform an extensive biodistribution study by PET/CT. The DDS biodistribution profile changes with different administration methods. Once administered at therapeutic doses, the DDS showed a marginal beneficial effect on 4T1 tumor bearing mice, a syngeneic and orthotopic model of triple negative breast cancer, with survival extended by 1 week and 2 days in 20% of the mice. This is encouraging given the aggressiveness of the 4T1 tumor. Furthermore, our DDS was well tolerated, ruling out concerns regarding the toxicity of carbon nanotubes.

Objective: To describe smoking behaviours of patients with incident cancer attending an Italian cancer centre and to examine changes in their smoking habits within 12 months from cancer diagnosis, evaluating determinants of smoking cessation. Methods: A hospital-based prospective cohort included patients hospitalized in an Italian cancer centre (2016–2018). Patients were mostly female (74%) and included a limited proportion of aerodigestive cancers (7%). Face-to-face interviews were performed during hospital stay to gather information on patient characteristics and smoking history. Changes in smoking habits were assessed through telephone interviews at 3, at 6, and at 12 months after cancer diagnosis. Results: Among 1011 enrolled patients, 222 (22%) were current smokers at cancer diagnosis. Smoking prevalence was high in male patients (30%), in patients Conclusions: Our results highlighted that 62% of smoking patients with cancer did not quit the habit. Smoking cessation programs targeted to patients with cancer need intensification, particularly for those who may underestimate smoking effects after diagnosis.

Bacterial canker disease caused by Pseudomonas syringae pv. actinidiae (Psa) biovar 3 involved all global interest since 2008. We have found that in Psa3 genome, similarly to other P. syringae, there are three putative genes, lscα, lscβ and lscγ, coding for levansucrases. These enzymes, breaking the sucrose moiety and releasing glucose can synthetize the fructose polymer levan, a hexopolysaccharide that is well known to be part of the survival strategies of many different bacteria. Considering lscα non-coding because of a premature stop codon, in the present work we cloned and expressed the two putatively functional levansucrases of Psa3, lscβ and lscγ, in E. coli and characterized their biochemical properties such as optimum of pH, temperature and ionic strength. Interestingly, we found completely different behaviour for both sucrose splitting activity and levan synthesis between the two proteins; lscγ polymerizes levan quickly at pH 5.0 while lscβ has great sucrose hydrolysis activity at pH 7.0. Moreover, we demonstrated that at least in vitro conditions, they are differentially expressed suggesting two distinct roles in the physiology of the bacterium.

Overcoming anticancer drug resistance is a major challenge in cancer therapy, requiring innovative strategies that consider the extensive tumor heterogeneity and adaptability. We provide recent evidence highlighting the key role of amino acid (AA) metabolic reprogramming in cancer cells and the supportive microenvironment in driving resistance to anticancer therapies. AAs sustain the acquisition of anticancer resistance by providing essential building blocks for biosynthetic pathways and for maintaining a balanced redox status, and modulating the epigenetic profile of both malignant and non-malignant cells. In addition, AAs support the reduced intrinsic susceptibility of cancer stem cells to antineoplastic therapies. These findings shed new light on the possibility of targeting nonresponding tumors by modulating AA availability through pharmacological or dietary interventions.

Cancer-associated fibroblasts (CAFs) are one of the main components of the stromal compartment in the tumor microenvironment (TME) and the crosstalk between CAFs and cancer cells is essential for tumor progression and aggressiveness. Cancer cells mediate an activation process, converting normal fibroblasts into CAFs, that are characterized by modified expression of many proteins and increased production and release of microvesicles (MVs), extracellular vesicles generated by outwards budding from the cell membrane. Recent evidence underlined that the uptake of CAF-derived MVs changes the overall protein content of tumor cells. In this paper, we demonstrate that tumor activated fibroblasts overexpress Galectin-1 (Gal-1) and consequently release MVs containing increased levels of this protein. The uptake of Gal-1 enriched MVs by tumor cells leads to the upregulation of its intracellular concentration, that strongly affects cancer cell migration, while neither proliferation nor adhesion are altered. Accordingly, tumor cells co-cultured with fibroblasts silenced for Gal-1 have a reduced migratory ability. The present work reveals the key role of an exogenous protein, Gal-1, derived from activated fibroblasts, in cancer progression, and contributes to clarify the importance of MVs-mediated protein trafficking in regulating tumor-stroma crosstalk.

Exosomes (Exos) have been reported to promote pre-metastatic niche formation, proliferation, angiogenesis and metastasis. We have investigated the role of uPAR in melanoma cell lines-derived Exos and their pro-angiogenic effects on human microvascular endothelial cells (HMVECs) and endothelial colony-forming cells (ECFCs). Melanoma Exos were isolated from conditioned media of A375 and M6 cells by differential centrifugation and filtration. Tunable Resistive Pulse Sensing (TRPS) and Nanoparticle tracking analysis were performed to analyze dimension and concentration of Exos. The CRISPR–Cas 9 technology was exploited to obtain a robust uPAR knockout. uPAR is expressed in melanoma Exos that are internalized by HMVECs and ECFCs, enhancing VE-Cadherin, EGFR and uPAR expression in endothelial cells that undergo a complete angiogenic program, including proliferation, migration and tube formation. uPAR loss reduced the pro-angiogenic effects of melanoma Exos in vitro and in vivo by inhibition of VE-Cadherin, EGFR and uPAR expression and of ERK1,2 signaling in endothelial cells. A similar effect was obtained with a peptide that inhibits uPAR–EGFR interaction and with the EGFR inhibitor Gefitinib, which also inhibited melanoma Exos-dependent EGFR phosphorylation. This study suggests that uPAR is required for the pro-angiogenic activity of melanoma Exos. We propose the identification of uPAR-expressing Exos as a potentially useful biomarker for assessing pro-angiogenic propensity and eventually monitoring the response to treatment in metastatic melanoma patients. Electronic supplementary material The online version of this article (10.1007/s00018-020-03707-4) contains supplementary material, which is available to authorized users.

Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1-17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes.

The increasing attention for metformin as anticancer drug, combined with its high doses necessary to exploit its action, makes interesting the preparation of carbon nanotubes (CNT) derivatives decorated with this drug. In this work, the preparation of metformin salt with oxidized CNT is described together with viability test in three different cell lines. Although the tests were performed at concentration 500 times lower than that used with free metformin, a dose dependent effect was evidenced. However, cytofluorimetric experiments revealed, unexpectedly, that metformin-CNT salts do not pass the cell membranes of all the six model cancer cell lines studied.

Hit, Lead & Candidate Discovery Protein tyrosine phosphatase 1B (PTP-1B) has attracted interest as a novel target for the treatment of type 2 diabetes, this because its role in the insulin-signaling pathway as a negative regulator. Thus, the aim of current work was to obtain seven ursolic acid derivatives as potential antidiabetic agents with PTP-1B inhibition as main mechanism of action. Furthermore, derivatives 1-7 were submitted in vitro to enzymatic PTP-1B inhibition being 3, 5, and 7 the most active compounds (IC50 = 5.6, 4.7, and 4.6 μM, respectively). In addition, results were corroborated with in silico docking studies with PTP-1B orthosteric site A and extended binding site B, showed that 3 had polar and Van der Waals interactions in both sites with Lys120, Tyr46, Ser216, Ala217, Ile219, Asp181, Phe182, Gln262, Val49, Met258, and Gly259, showing a docking score value of -7.48 Kcal/mol, being more specific for site A. Moreover, compound 7 showed polar interaction with Gln262 and Van der Waals interactions with Ala217, Phe182, Ile219, Arg45, Tyr46, Arg47, Asp48, and Val49 with a predictive docking score of -6.43 kcal/mol, suggesting that the potential binding site could be localized in the site B adjacent to the catalytic site A. Finally, derivatives 2 and 7 (50 mg/kg) were selected to establish their in vivo antidiabetic effect using a noninsulin-dependent diabetes mice model, showing significant blood glucose lowering compared with control group (p

Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually available for its treatment, in the long term, they show limited effectiveness. Most traditional drugs are designed to act on a specific biological target, but the complexity of the current pathologies has demonstrated that molecules hitting more than one target may be safer and more effective. The purpose of this review is to shed light on the natural compounds known as α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) dual-inhibitors that could be used as lead compounds to generate new multitarget antidiabetic drugs for treatment of T2D.

Batches of oxidized multiwalled carbon nanotubes differing in length were adopted to prepare two drug delivery systems (DDS) loaded with doxorubicin. The different internalization of the two batches, verified by atomic emission spectroscopy onto cell lysates, was also confirmed by the different toxicity of the same DDS loaded with doxorubicin. I n vitro experiments evidenced, after 48 h of incubation, the superior efficacy of the shortest nanotubes. However, upon prolonging the incubation time up to 72 h the difference in efficiency was minimized due to the spontaneous release of doxorubicin by the non-internalized long nanotubes.

New 4-{[5-arylidene-2-(4-fluorophenylimino)-4-oxothiazolidin-3-yl]methyl}benzoic acids (5) and 2-thioxo-4-thiazolidinone analogues (6) were synthesised as a part of a continuing search for new inhibitors of protein tyrosine phosphatase 1B (PTP1B), an enzyme which is implicated in metabolic disorders and inflammatory signaling. Most of the tested compounds were shown to be potent PTP1B inhibitors. Moreover, their inhibition mechanism was markedly influenced by the substituents in the positions 2 and 5, as kinetic studies indicated. Docking experiments suggested that certain derivatives 5 and 6 may efficiently fit into an allosteric site positioned between the β-sheet including Leu71 and Lys73 and a lipophilic pocket closed by the loop consisting of Pro210 to Leu 204. In cellular assays, several of these new 4-thiazolidinone derivatives showed insulinomimetic and anti-inflammatory properties. Out of them, compound 5b exhibited the most promising profile, being able to promote the activation of both insulin receptor and downstream Akt protein as well as to increase 2-deoxyglucose cellular uptake. Interestingly, compound 5b was also able to interrupt critical events in inflammatory signaling.

Sourdough fermentation influences several properties of leavened baked goods also because Lactic acid bacteria (LAB) and yeasts produce bioactive peptides with a positive effect on human health. In an early study, three Lactobacilli strains (L. farciminis H3 and A11 and L. sanfranciscensis I4) possessing different proteolytic activities were used to produce sourdoughs containing peptides equipped with anti-inflammatory and/or antioxidant properties. This work was aimed to assess whether these properties could be retained after cooking. The selected LABs were used to produce breads from which low molecular weight (LMW-) peptides were extracted. The results provide solid proofs of keeping both antioxidant and anti-inflammatory activities of peptides from cooked products. Sequences of LMW-peptides either from doughs and breads were determined by mass spectrometry: differences have been noticed in amino acidic composition and in sequences, however, all the strains produce peptides equipped with antioxidant and anti-inflammatory activities.

Chemoresistance is the primary cause of chemotherapy failure. Compelling evidence shows that micro RNAs (miRNAs) contribute to reprogram cancer cells toward a resistant phenotype. We investigate the role of miRNAs in the response to acute treatment with 5-FU in colon cancer-resistant cells. We performed a global gene expression profile for the entire miRNA genome and found a change in the expression of four miRNAs following acute treatment with 5-FU. Among them, we focused on miR-210-3p, previously described as a key regulator of DNA damage repair mechanisms and mitochondrial metabolism. We show that miR-210-3p downregulation enables resistant cells to counteract the toxic effect of the drug increasing the expression of RAD-52 protein, responsible for DNA damage repair. Moreover, miR-210-3p downregulation enhances oxidative phosphorylation (OXPHOS), increasing the expression levels of succinate dehydrogenase subunits D, decreasing intracellular succinate levels and inhibiting HIF-1α expression. Altogether, these adaptations lead to increased cells survival following drug exposure. These evidence suggest that miR-210-3p downregulation following 5-FU sustains DNA damage repair and metabolic adaptation to counteract drug treatment.

It is estimated that chronic inflammation contributes to nearly 25% of human cancers. Inflammation of the gastric mucosa is dependent on various modulatory components such as microbes, environment, and host predisposition. Helicobacter pylori (H. pylori) can initiate and sustain gastric inflammation by its virulence factors as well as by altered cellular pathways that are involved in the restoration of the tissue homeostasis after infection. Indeed, in an attempt to repair injured mucosa, immune system may contribute to gastric cancer development through its physiological pro-inflammatory and anti-inflammatory activities which, particularly in a setting of chronic antigenic stimulation, can turn in pro-tumorigenic effects. In this chapter some of the mechanisms connected to H. pylori-related inflammation will be depicted, also focusing on microenvironmental cellular and soluble driving factors recently highlighted in gastric cancer promotion.

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.

// Massimiliano Berretta 1 , Chiara Della Pepa 2 , Paolo Tralongo 3 , Alberto Fulvi 4 , Ferdinando Martellotta 1 , Arben Lleshi 1 , Guglielmo Nasti 5 , Rossella Fisichella 6 , Carmela Romano 5 , Chiara De Divitiis 5 , Rosaria Taibi 1 , Francesco Fiorica 7 , Raffaele Di Francia 8, 9 , Anna Di Mari 3 , Lino Del Pup 10 , Anna Crispo 11 , Paolo De Paoli 12 , Adriano Santorelli 13 , Vincenzo Quagliariello 5 , Rosario Vincenzo Iaffaioli 5 , Umberto Tirelli 1 , Gaetano Facchini 2 1 Department of Medical Oncology, National Cancer Institute, Aviano (PN), Italy 2 Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, Italy 3 Division of Medical Oncology, “Umberto I” Hospital, Syracuse, Italy 4 Department of Medicine and Surgery of Integrated Treatment, Division of Thoracic Oncology, “San Camillo Forlanini” Hospital, Rome, Italy 5 Department of Abdominal Oncology, Division of Medical Oncology B, National Cancer Institute, “G. Pascale” Foundation, Naples, Italy 6 Department of Surgery, University of Catania, Catania, Italy 7 Department of Radiation Oncology University Hospital Ferrara, Division of Radiotherapy, “Arcispedale Sant’Anna” Hospital, Ferrara, Italy 8 Department of Hematology, Istituto Nazionale Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Naples, Italy 9 Gruppo Oncologico Ricercatori Italiani, GORI, Pordenone, Italy 10 Division of Gynaecological Oncology, National Cancer Institute, Aviano (PN), Italy 11 Unit of Epidemiology, Struttura Complessa di Statistica Medica, Biometria e Bioinformatica, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Naples, Italy 12 Scientific Directorate, National Cancer Institute, Aviano (PN), Italy 13 Department of Plastic Surgery, Regenerative Medicine, Health Park Hospital, Naples, Italy Correspondence to: Massimiliano Berretta, email: mberretta@cro.it Keywords: complementary medicine, alternative medicine, survey, cancer, treatment Received: October 13, 2016 Accepted: November 20, 2016 Published: December 25, 2016 ABSTRACT Introduction: Complementary and Alternative Medicine (CAM) include a wide range of products (herbs, vitamins, minerals, and probiotics) and medical practices, developed outside of the mainstream Western medicine. Patients with cancer are more likely to resort to CAM first or then in their disease history; the potential side effects as well as the costs of such practices are largely underestimated. Patients and method: We conducted a descriptive survey in five Italian hospitals involving 468 patients with different malignancies. The survey consisted of a forty-two question questionnaire, patients were eligible if they were Italian-speaking and receiving an anticancer treatment at the time of the survey or had received an anticancer treatment no more than three years before participating in the survey. Results: Of our patients, 48.9% said they use or have recently used CAM. The univariate analysis showed that female gender, high education, receiving treatment in a highly specialized institute and receiving chemotherapy are associated with CAM use; at the multivariate analysis high education (Odds Ratio, (OR): 1.96 95% Confidence Interval, CI, 1.27-3.05) and receiving treatment in a specialized cancer center (OR: 2.75 95% CI, 1.53-4.94) were confirmed as risk factors for CAM use. Conclusion: Roughly half of our patients receiving treatment for cancer use CAM. It is necessary that health professional explore the use of CAM with their cancer patients, educate them about potentially beneficial therapies in light of the limited available evidence of effectiveness, and work towards an integrated model of health-care provision.

The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the outcome of HIV-infected patients by prolonging their survival. The increase in life expectancy has led to an increased risk of non-AIDS-related mortality and morbidity, including cardiovascular diseases, neurocognitive diseases, neuroendocrine dysfunctions and cancer. Areas covered: The GICAT (Italian Cooperation Group on AIDS and Tumors) has demonstrated that patients who receive a multidisciplinary approach with the combination of anticancer agents (AC) and HAART can achieve better responses and survival rates than patients who receive AC alone. The first obstacle for the oncologist to plan treatment for cancer HIV-patients is the preliminary evaluation of drug-drug interactions between AC and HAART. Recent progress in pharmacogenomics could provide a new approach for personalized treatments. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, to maximize the efficacy of both concomitant therapy and to minimize the risk of DDIs, a currently useful list of pharmacogenomic markers of key metabolic enzymes is provided. Expert opinion: In this scenario, the importance of cooperation between oncologists and other health specialists (i.e., infectivologists, pharmacists, genetics and lab specialists) must not be underestimated in the management of these patients with the aim of planning an individual treatment strategy.

The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed–Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20–40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.

Originally identified as a low molecular weight acid phosphatase, LMW-PTP is actually a protein tyrosine phosphatase that acts on many phosphotyrosine-containing cellular proteins that are primarily involved in signal transduction. Differences in sequence, structure, and substrate recognition as well as in subcellular localization in different organisms enable LMW-PTP to exert many different functions. In fact, during evolution, the LMW-PTP structure adapted to perform different catalytic actions depending on the organism type. In bacteria, this enzyme is involved in the biosynthesis of group 1 and 4 capsules, but it is also a virulence factor in pathogenic strains. In yeast, LMW-PTPs dephosphorylate immunophilin Fpr3, a peptidyl-prolyl-cis-trans isomerase member of the protein chaperone family. In humans, LMW-PTP is encoded by the ACP1 gene, which is composed of three different alleles, each encoding two active enzymes produced by alternative RNA splicing. In animals, LMW-PTP dephosphorylates a number of growth factor receptors and modulates their signalling processes. The involvement of LMW-PTP in cancer progression and in insulin receptor regulation as well as its actions as a virulence factor in a number of pathogenic bacterial strains may promote the search for potent, selective and bioavailable LMW-PTP inhibitors.

Diabetes mellitus (DM) is associated with an elevated risk of cancer. The aim of this study was to assess cancer risk and survival in individuals with type 2 DM (T2DM) in Friuli Venezia Giulia, Italy. A retrospective population-based cohort study of 32,247 T2DM patients aged 40-84 years was conducted through a record linkage of local healthcare databases and cancer registry for the period 2002-2009. Standardized incidence ratios (SIRs) with 95% confidence intervals (95%CIs) and 5-year survival probabilities after T2DM and cancer diagnosis were computed. The SIRs for all cancers (n=2069) was 1.28 (95%CI: 1.23-1.34). The highest SIRs were observed for cancers of the liver, female genital organs, small intestine, and pancreas. After 3 years from T2DM diagnosis, a reduced risk of prostate cancer (SIR=0.73, 95%CI: 0.54-0.96) was found in men aged 65-74 years, and a higher risk for breast cancer (SIR=1.24, 95%CI: 1.00-1.52) was found among T2DM female patients. The overall 5-year survival after T2DM was 88.7%. Furthermore, T2DM appeared to have a negative effect on survival of women with breast cancer. This population-based study confirmed that T2DM patients are at increased risk of several cancers, and of premature death in women with breast cancer.

Morin is a natural polyphenol, originally isolated from members of the Moraceae family that can be extracted from leaves, fruits, stems and branches of numerous plants. Several evidence have demonstrated that Morin could have a beneficial effect on several human diseases. In fact, Morin exerts antioxidant, antidiabetic, anti-inflammatory, antitumoral, antihypertensive, antibacterial, hypouricemic, and neuroprotective effects, by modulating the activity of many enzymes. In some cases, Morin shows a systemic protective action, reducing negative side effects of several drugs, without interfering with their functions. In addition, in vitro and in vivo studies demonstrated that Morin exhibits very low toxicity levels and its chronic administration is well tolerated. All these findings suggest that Morin could be used, either alone or in combination with other drugs, to prevent many human pathologies.

Two newly synthesized nonavalent polyhydroxylated pyrrolidine iminosugars are the first examples of multivalent inhibitors of GALNS and IDS lysosomal enzymes, whose deficiency leads to Morquio A syndrome and Hunter disease, respectively, and pave the way to a pharmacological chaperone or stabilizing enzyme therapy for these LSDs.

In mammalian cells, tyrosine phosphorylation is one of the main mechanisms responsible for regulating signal transduction pathways and key cellular functions. Moreover, recent studies demonstrated that tyrosine phosphorylation influences the activity of some metabolic enzymes, even if it remains to be clarified whether tyrosine phosphorylation can be considered a general mechanism involving most of the metabolic enzymes or only a subset of these. To elucidate this aspect, we conducted a two-step analysis. First, we analyzed literature to identify all the metabolic enzymes whose activity is affected by tyrosine phosphorylation. Second, we crossed these data with those obtained from the PhosphoSitePlus database analysis. Collected information was used to depict an exhaustive map showing the real spread of tyrosine phosphorylation among metabolic enzymes. In summary, data reported in this review highlight that tyrosine phosphorylation is not a sporadic event but a widespread post-translational modification, which is essential to promote the metabolic reprogramming of cancer cells.

The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids. All the target compounds behave as good GCase inhibitors, with IC50 in the micromolar range. Moreover, compound 11a behaves as a PC in fibroblasts derived from Gaucher patients bearing the N370/RecNcil mutation and the homozygous L444P mutation, rescuing the activity of the deficient enzyme by up to 1.9- and 1.8-fold, respectively. Rescues of 1.2-1.4-fold were also observed in wild-type fibroblasts, which is important for targeting sporadic forms of PD.

Background L-Homocysteine (Hcy) is a non-proteinogenic α-amino acid synthesized from dietary methionine. In healthy humans, high Hcy levels are a risk factor for cardiovascular diseases, stroke and type 2 diabetes. A recent study reports that Hcy reacts with Cys10 of transthyretin (TTR), generating a stable covalent adduct. However, to date the effect of S-homocysteinylation on TTR conformational stability remains unknown. Methods The effect of Hcy on the conformational properties of wt- and L55P-TTR were analysed using a set of biophysical techniques. The cytotoxicity of S-homocysteinylated L55P-TTR was also evaluated in the HL-1 cardiomyocyte cell line, while the effects of the assemblies on kinematic and dynamics properties of cardiac muscle cells were analysed in cardiomyocyte syncytia. Results We found that Hcy stabilizes tetrameric wt-TTR, while it destabilizes the tetrameric structure of the L55P mutant, promoting the accumulation of self-assembly-prone monomeric species. Conclusions Our study demonstrated that S-homocysteinylation of the L55P-TTR mutant impairs protein stability, favouring the appearance of toxic monomers. Interestingly, S-homocysteinylation affected only mutant, not wt-TTR. Moreover, we also show that assemblies of S-homocysteinylated L55P-TTR impair cardiomyocytes functional parameters. General significance Our study offers new insights on the negative impact of S-homocysteinylation on L55P-TTR stability, whose aggregation is considered the causative agent of a form of early-onset familial amyloid polyneuropathy and cardiomyopathy. Our results suggest that high homocysteine levels are a further risk factor for TTR cardiomyopathy in patients harbouring the L55P-TTR mutation.

Roberto Burro,1 Ugo Savardi,1 Maria Antonietta Annunziata,2 Paolo De Paoli,2 Ivana Bianchi3 1Department of Human Sciences, University of Verona, 37129 Verona, Italy; 2National Cancer Institute IRCCS “Centro di Riferimento Oncologico” (CRO), 33080 Aviano (PN), Italy; 3Department of Humanities (section Philosophy and Human Sciences), University of Macerata, 62100 Macerata, Italy Background: Healthcare staff should be aware of the importance that patients may attach to the words that are used to convey information. This is relevant in terms of the patients’ understanding. Modeling how people understand the information conveyed in a medical context may help health practitioners to better appreciate the patients’ approach. Purpose: 1) Analyze the participants’ self-reported perception of the type of information provided in an oncological scenario in terms of three dimensions: impairment to their health, risks associated with the disease itself and commitment required to undergo the treatment; and 2) show the benefits of using Rasch scaling for the analysis of the data. Starting from a survey, Rasch scaling produces a unidimensional logit-interval scale relating to the extent to which each item conveys a latent dimension. These were related to structure, in particular concerning communication by means of opposite vs. unipolar language. Subjects and methods: The participants rated 82 items of information in a questionnaire regarding their perception of impairment to their health (H) and the risks (R) and commitment relating to the treatment prescribed (T). Results: The scaling produced an item bank for healthcare staff to consult in order to estimate the importance the recipient would be likely to attach to the vocabulary used and the likely impact of the information in terms of the patient’s condition. Furthermore, the use of opposites was generally associated with a clearer impression of whether the information given was generally only very negative or slightly negative, whereas ‘neutral’ information was often perceived as being very negative. Actual findings: Is possible to estimate people’s understanding more precisely (in terms of H, R and T) which can help healthcare practitioners to modulate the way they convey information. Limitations: The participants in the study were healthy volunteers and the context was simulated. Keywords: Rasch model, simulated oncological scenario, perceived severity of impairment to health, perception of risk, perceived commitment to the treatment, opposites

Type 2 diabetes mellitus (T2DM) is the most prevalent disease and becoming a serious public health threat worldwide. It is a severe endocrine metabolic disorder that has the ability to induce serious complications in all kinds of organs. Although mechanisms of anti-diabetics have been described before, we focus here on the cellular and physiological mechanisms involved in the modulation of insulin and glucose blood levels. As obesity and inflammation are intimately associated with the development of T2DM, their possible relationships are also described. The effects of gut microbiota on insulin resistance have been recently investigated in clinical trials, and we discuss the potential mechanisms by which gut microbiota may improve glucose handling, especially via the metabolism of ingested phytochemicals. Among the historically supported effects of phytochemicals, their therapeutic potential for T2DM leads to consider these natural products as an important pool for the identification of novel anti-diabetic drug leads. This current research extends the descriptions of anti-diabetic effects of plants that are used in traditional medicines or as nutraceuticals. The objective of the present review is to make a systematic report on glucose metabolism in T2DM as well as to explore the relationships between natural phytochemicals and glucose handling.

In this study, we synthesized five N-Boc-L-tyrosine-based analogues to glitazars. The in vitro effects of compounds 1–5 on protein tyrosine phosphatase 1B (PTP-1B), peroxisome proliferator-activated receptor alpha and gamma (PPARα/γ), glucose transporter type-4 (GLUT-4) and fatty acid transport protein-1 (FATP-1) activation are reported in this paper. Compounds 1 and 3 were the most active in the in vitro PTP-1B inhibition assay, showing IC50s of approximately 44 μM. Treatment of adipocytes with compound 1 increased the mRNA expression of PPARγ and GLUT-4 by 8- and 3-fold, respectively. Moreover, both compounds (1 and 3) also increased the relative mRNA expression of PPARα (by 8-fold) and FATP-1 (by 15-fold). Molecular docking studies were performed in order to elucidate the polypharmacological binding mode of the most active compounds on these targets. Finally, a murine model of hyperglycemia was used to evaluate the in vivo effectiveness of compounds 1 and 3. We found that both compounds are orally active using an exploratory dose of 100 mg/kg, decreasing the blood glucose concentration in an oral glucose tolerance test and a non-insulin-dependent diabetes mellitus murine model. In conclusion, we demonstrated that both molecules showed strong in vitro and in vivo effects and can be considered polypharmacological antidiabetic candidates.

This work presents the synthesis of two hybrid compounds (1 and 2) with thiazolidine-2,4-dione structure as a central scaffold which were further screened in combo (in vitro as PTP-1B inhibitors, in vivo antihyperglycemic activity, in silico toxicological profile and molecular docking). Compound 1 was tested in the enzymatic assay showing an IC50 = 9.6 ± 0.5 μM and compound 2 showed about a 50% of inhibition of PTP-1B at 20 μM. Therefore, compound 1 was chosen to test its antihyperglycemic effect in a rat model for non-insulin-dependent diabetes mellitus (NIDDM), which was determined at 50 mg/kg in a single dose. The results indicated that compound showed a significant decrease of plasma glucose levels that reached 34%, after a 7 h post-administration. Molecular docking was employed to study the inhibitory properties of thiazolidine-2,4-dione derivatives against Protein Tyrosine Phosphatase 1B (PDB ID: 1c83). Concerning to the two binding sites in this enzyme (sites A and B), compound 1 has shown the best docking score, which indicates the highest affinity. Finally, compounds 1 and 2 have demonstrated an in silico satisfactory pharmacokinetic profile. This shows that it could be a very good candidate or leader for new series of compounds with this central scaffold.

This paper investigates the phenolic composition of 17 monocultivar commercial cold-pressed grape seed oils. Chromatographic profiles showed the presence of more than 28 molecules, 11 of which were successfully identified by HPLC-DAD-MS-TOF and HPLC-FLD analysis. Pinoresinol, ethyl caffeate and ethyl gallate were detected for the first time in these oils. The total phenolic content ranged between 0.83 mg/kg for Viognier sample to 15.16 mg/kg for Merlot org sample. The detected ethyl esters can be suggested as markers to evaluate the intensity of fermentation in grape seeds before oil extraction, and to control the sensorial quality of the produced oils. In addition, the inhibitory power of these phenolic extracts against Protein Tyrosine Phosphatase 1B enzyme (PTP-1B), overexpressed in type-two diabetes, was investigated for the first time. Data highlighted a good correlation between total phenolic content and inhibitory power, with pinoresinol, p-coumaric acid and quercetin making the greater contributions.

In 2012, the “Centro di Riferimento Oncologico” (CRO) National Cancer Institute joined the accreditation program of the Organisation of European Cancer Institutes (OECI) and was one of the first institutes in Italy to receive recognition as a Comprehensive Cancer Center. At the end of the project, a strengths, weaknesses, opportunities, and threats (SWOT) analysis aimed at identifying the pros and cons, both for the institute and of the accreditation model in general, was performed. The analysis shows significant strengths, such as the affinity with other improvement systems and current regulations, and the focus on a multidisciplinary approach. The proposed suggestions for improvement concern mainly the structure of the standards and aim to facilitate the assessment, benchmarking, and sharing of best practices. The OECI accreditation model provided a valuable executive tool and a framework in which we can identify several important development projects. An additional impact for our institute is the participation in the project BenchCan, of which the OECI is lead partner.

Fibroblasts are the most abundant cells in connective tissue and, with fibrillar extracellular matrix, form the structural scaffolding of organs. In solid tumors, interaction with cancer cells induces fibroblasts transdifferentiation into an activated form, which become a fundamental part of the tumor stroma. Within tumor microenvironment stromal and cancer cells engage a crosstalk that is mediated by soluble factors, cellcell contacts and extracellular vesicles trafficlking. Here we report that fibroblasts have the ability to transfer a remarkable amount of proteins and lipids to neighboring cells, in an ectosome-dependent fashion, identifying a novel and native property of these cells. Cancer-associated fibroblasts show an enhanced production and delivering of ectc:Jsomes to cancer cells compared to normal fibroblasts. As a consequence of this phenomenon, tumor cells increase their proliferation rate, indicating that ectosome-mediated trafficking could be a relevant mechanism mediating the trophic function of activated connective tissue on tumor cells.

Objective: To evaluate whether plasma cell-free DNA (cfDNA) was related to clinical outcome in inoperable stage I non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiotherapy (SBRT).Materials and methods: Plasma cfDNA was assessed at baseline, before the last day and 45 days after the end of SBRT, in 22 NSCLC patients. Twenty-two healthy controls were also evaluated.Results: Plasma cfDNA was higher in patients than in controls. An association with unfavourable disease-free survival was found for continuous baseline cfDNA increments (HR = 5.9, 95%CI: 1.7–19.8, p = 0.04).Conclusion: Plasma cfDNA may be a promising prognostic biomarker in high-risk NSCLC patients.

This study aimed to evaluate plasma concentration of selected cancer-associated inflammatory and immune-modulated cytokines in HIV+ patients with advanced Kaposi sarcoma (KS), and to explore candidate biomarkers capable of predicting clinical outcome in response to chemotherapy (CT) plus combination antiretroviral therapy (cART). Thirty-seven plasma cytokines/chemokines were assessed by Luminex technology in 27 consecutive HIV+ KS patients, followed-up during CT and cART of maintanence (m-cART). Associations between plasma concentration of biomarkers and patient clinical response to m-cART were evaluated by means of Hazard Ratios (HRs) and corresponding 95% Confidence Intervals (CIs). Plasma baseline concentration of Granulocyte colony-stimulating factor (G-CSF), Hepatocyte growth factor (HGF) and endoglin were found to be associated with m-cART clinical response (HR:1.56, 95%CI:1.09–2.22, p = 0.01; HR:0.32, 95% CI:0.10–0.99, p = 0.05; HR:0.72, 95% CI:0.54–0.96, p = 0.03, respectively). The multivariate analysis confirmed the associations of baseline plasma G-CSF and HGF concentration with m-cART clinical complete remission response (HR:1.78, 95% CI:1.15–2.74, p = 0.009; HR:0.19, 95% CI:0.04–0.95, p = 0.04). Our exploratory study suggested that plasma G-CSF, HGF and endoglin may be novel predictors of clinical response during m-cART in HIV+ KS patients. Nonetheless, these findings should be further validated in an independent population study.

Aim: A dose-response meta-analysis was conducted in order to summarize the evidence from prospective cohort studies regarding the association between coffee intake and breast cancer risk. Methods: A systematic search was performed in electronic databases up to March 2017 to identify relevant studies; risk estimates were retrieved from the studies and linear and non-linear dose-response analysis modelled by restricted cubic splines was conducted. A stratified and subgroup analysis by menopausal and estrogen/progesterone receptor (ER/PR) status, smoking status and body mass index (BMI) were performed in order to detect potential confounders. Results: A total of 21 prospective studies were selected either for dose-response, the highest versus lowest category of consumption or subgroup analysis. The dose-response analysis of 13 prospective studies showed no significant association between coffee consumption and breast cancer risk in the non-linear model. However, an inverse relationship has been found when the analysis was restricted to post-menopausal women. Consumption of four cups of coffee per day was associated with a 10% reduction in postmenopausal cancer risk (relative risk, RR 0.90; 95% confidence interval, CI 0.82 to 0.99). Subgroup analyses showed consistent results for all potential confounding factors examined. Conclusions: Findings from this meta-analysis may support the hypothesis that coffee consumption is associated with decreased risk of postmenopausal breast cancer.

The increasing use of genomics to define the pattern of actionable mutations and to test and validate new therapies for individual cancer patients, and the growing application of liquid biopsy to dynamically track tumor evolution and to adapt molecularly targeted therapy according to the emergence of tumor clonal variants is shaping modern medical oncology., In order to better describe this new therapeutic paradigm we propose the term "Liquid dynamic medicine" in the place of "Personalized or Precision medicine". Clinical validation of the "Liquid dynamic medicine" approach is best captured by N-of-1 trials where each patient acts as tester and control of truly personalized therapies. © 2017 The Author(s).

Primary effusion lymphoma (PEL) is a rare B-cell lymphoid neoplasm mainly associated with HIV infection, presenting as pleural, peritoneal, and pericardial effusions. A defining property of PEL is its consistent association with Kaposi sarcoma associated herpesvirus (KSHV) infection, and, in most cases, Epstein Barr virus (EBV) co-infection. On these grounds, a review of the literature related to viral cooperation and lymphomagenesis can help to understand the complex interplay between KSHV and EBV in PEL pathogenesis. Areas covered: In this review, the authors highlight clinical, pathologic, genetic and proteomic features of PEL, in the context of viral cooperation in PEL lymphomagenesis. Expert commentary: Tumour cells are characterized by the overexpression of genes that are involved in inflammation and invasion. Coherently, PEL secretomes are enriched in proteins probably responsible for the particular tropism (cell adhesion and migration) of PEL cells. The development of PEL in HIV+ patients is multifactorial and involves a complex interplay among co-infection with oncogenic viruses (EBV and KSHV), inflammatory factors, and environmental conditions.

The study of compounds able to interfere in various ways with amyloid aggregation is of paramount importance in amyloid research. Molecules characterized by a 4-thiaflavane skeleton have received great attention in chemical, medicinal, and pharmaceutical research. Such molecules, especially polyhydroxylated 4-thiaflavanes, can be considered as structural mimickers of several natural polyphenols that have been previously demonstrated to bind and impair amyloid fibril formation. In this work, we tested five different 4-thiaflavanes on the hen egg-white lysozyme (HEWL) amyloid model for their potential anti-amyloid properties. By combining a thioflavin T assay, atomic force microscopy, and a cell toxicity assay, we demonstrated that such compounds can impair the formation of high-order amyloid aggregates and mature fibrils. Despite this, the tested 4-thiaflavanes, although non-toxic per se, are not able to prevent amyloid toxicity on human neuroblastoma cells. Rather, they proved to block early aggregates in a stable, toxic conformation. Accordingly, 4-thiaflavanes can be proposed for further studies aimed at identifying blocking agents for the study of toxicity mechanisms of amyloid aggregation.

Background.The impact of highly active antiretroviral therapies(HAART)ontheriskofnon-AIDS-definingcancers(NADCs) and the role of biological and clinical factors in their pathogenesis are debated issues. The purpose of this review is to examine the epidemiology, etiology, and not-yet-defined pathogeniccharacteristicsofNADCsanddiscusstopicssuchas treatmentstrategies,comorbidity,andmultidruginteractions. Four types of NADCs that deserve special attention are examined: anal cancer, Hodgkin lymphoma (HL), hepatocellular carcinoma, and lung cancer. Methods.The PubMed database and the Cochrane Library were searched by focusing on NADCs and on the association amongNADCs,HAART,aging,and/orchronicinflammation.All articleswerereviewed toidentifythose reporting variables of interest. Results. NADC incidence is twofold higher in patients with HIV/AIDSthaninthecorrespondinggeneralpopulation,andthis elevated risk persists despite the use of HAART. The mechanismsthatHIVmayusetopromotethedevelopmentofNADCs are presently unclear; immunological mechanisms, either immunodeficiencyand/orimmunoactivation,mayplayarole. Conclusion. Recent clinical studies have suggested that equivalent antineoplastic treatment is feasible and outcome can be similar in HIV-infected patients on HAART compared with uninfectedpatients for the treatment of HL and anal and lung cancers. However, patients with advanced HIV disease and/or aging-related comorbidities are likely to experience worse outcomes and have poorer tolerance of therapy compared with those with less advanced HIV disease. The Oncologist 2014;19:1–8 ImplicationsforPractice:Thisreviewprovidesinformationontheepidemiologyofnon-AIDS-definingcancers(NADCs),important inviewofthechangingspectrumofAIDS-relatedmalignanciesresemblingcancerspresentinHIV-negativepopulation.HIVpatients with NADCs experience advanced stages at diagnosis, aggressive behaviors of the disease, poor prognoses, are frequently undertreatedanddieprematurely.ThedatareportedherehaveimplicationsinthemanagementofHIV-associatedcancers,since preventionandscreeningprogramsforHIV-infectedpersonsneedtobeenforced.Specialistsmustbeawarethatevidencessuggest that equivalent treatment is feasible, and outcomes can be similar, in HIV-infected patients on effective HAART compared to uninfected patients. Further progress in the treatment of NADCs strongly depends on prospective clinical trials, including drugdrug interaction studies.

Rationale, aims and objectives Pharmacovigilance (PV), or drug safety monitoring, aims to improve patient safety through the detection and management of drug-related adverse reactions. It is implemented both by spontaneous reporting of adverse drug reactions (ADRs) and by careful detection of signals suggestive of drug toxicity. PV is an important clinical topic in clinical practice and pharmacotherapy, assuring the maintenance of a safe risk/benefit ratio throughout the commercial life cycle of a drug. Methods We conducted a structured literature search on PubMed, Scopus, Cinahl and the Cochrane Library. We also performed manual searches in international databases of ADR individual reports to outline a structured profile on the topic. Our goal was to review key elements that affect safety monitoring of cancer drugs and their appropriate use, highlighting the strengths and weaknesses of PV in oncology. Results This paper provides an understanding of the methodologies used by PV in current clinical practice and particularly in cancer drug therapy; a focus upon reporting of ADRs by health professionals and patients; and a focus upon methods used by PV to detect new signals of risk/harm related to medicines utilization. Conclusion To our knowledge, few articles focus upon the importance of PV and post-marketing surveillance of cancer drug therapies. Structured management of spontaneous reports of ADRs and data collection is essential to monitoring the safe use of drugs in this field in which pharmacotherapy is affected by high incidence of drug-related complications and by a narrow benefit/risk ratio.