Showing papers by "Michele Caraglia published in 2017"

Micrornas in prostate cancer: an overview

Abstract: // Daniela Vanacore 1, 2, * , Mariarosaria Boccellino 2, * , Sabrina Rossetti 1, 3 , Carla Cavaliere 1, 4 , Carmine D’Aniello 1, 5 , Rossella Di Franco 1, 6 , Francesco Jacopo Romano 1 , Micaela Montanari 1, 7 , Elvira La Mantia 1, 8 , Raffaele Piscitelli 1, 9 , Flavia Nocerino 1, 10 , Francesca Cappuccio 1, 11 , Giovanni Grimaldi 1, 12 , Alessandro Izzo 1, 12 , Luigi Castaldo 1, 12 , Maria Filomena Pepe 1, 8 , Maria Gabriella Malzone 1, 8 , Gelsomina Iovane 3 , Gianluca Ametrano 1, 6 , Paola Stiuso 2 , Lucio Quagliuolo 2 , Daniela Barberio 1, 11 , Sisto Perdona 12 , Paolo Muto 6 , Maurizio Montella 10 , Piera Maiolino 9 , Bianca Maria Veneziani 7 , Gerardo Botti 8, 13 , Michele Caraglia 2 and Gaetano Facchini 1, 3 1 Progetto ONCONET2.0, Linea progettuale 14 per l’implementazione della Prevenzione e Diagnosi Precoce del Tumore alla Prostata e Testicolo, Regione Campania, Italy 2 Department of Biochemistry, Biophysics and General Pathology, University of Campania “L. Vanvitelli” Naples, Naples, Italy 3 Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy 4 Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto, Taranto, Italy 5 Division of Medical Oncology, A.O.R.N. dei COLLI “Ospedali Monaldi-Cotugno-CTO”, Napoli, Italy 6 Radiation Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy 7 Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy 8 Pathology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy 9 Pharmacy Unit, Istituto Nazionale Tumori, Istituto Nazionale Tumori-Fondazione G. Pascale, Naples, Italy 10 Epidemiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy 11 Psicology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’, IRCCS, Napoli, Italy 12 Division of Urology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy 13 Scientific Directorate, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, IRCCS, Naples, Italy * These authors have contributed equally to this work Correspondence to: Michele Caraglia, email: michele.caraglia@unina2.it , michele.caraglia@alice.it Keywords: microRNAs, prostate cancer, biomarkers, oncogenic miRNAs, tumor suppressor miRNAs Received: February 06, 2017 Accepted: March 25, 2017 Published: April 07, 2017 ABSTRACT Prostate cancer is the second highest cause of cancer mortality after lung tumours. In USA it affects about 2.8 million men and the incidence increases with age in many countries. Therefore, early diagnosis is a very important step for patient clinical evaluation and for a selective and efficient therapy. The study of miRNAs’ functions and molecular mechanisms has brought new knowledge in biological processes of cancer. In prostate cancer there is a deregulation of several miRNAs that may function as tumour suppressors or oncogenes. The aim of this review is to analyze the progress made to our understanding of the role of miRNA dysregulation in prostate cancer tumourigenesis.

Testicular cancer from diagnosis to epigenetic factors

Abstract: Testicular cancer (TC) is one of the most common neoplasms that occurs in male and includes germ cell tumors (GCT), sex cord-gonadal stromal tumors and secondary testicular tumors. Diagnosis of TC involves the evaluation of serum tumor markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, but clinically several types of immunohistochemical markers are more useful and more sensitive in GCT, but not in teratoma. These new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related cells but not in normal adult germ cells and they include PLAP, OCT3/4 (POU5F1), NANOG, SOX2, REX1, AP-2γ (TFAP2C) and LIN28. Gene expression in GCT is regulated, at least in part, by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. There are different epigenetic modifications in TG-subtypes that reflect the normal developmental switch in primordial germ cells from an under- to normally methylated genome. The main purpose of this review is to illustrate the findings of recent investigations in the classification of male genital organs, the discoveries in the use of prognostic and diagnostic markers and the epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and microRNAs (miRNAs).

Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action.

Abstract: Looking for new metal-based anticancer treatments, in recent years many ruthenium complexes have been proposed as effective and safe potential drugs. In this context we have recently developed a novel approach for the in vivo delivery of Ru(III) complexes, preparing stable ruthenium-based nucleolipidic nanoaggregates endowed with significant antiproliferative activity. Herein we describe the cellular response to our ruthenium-containing formulations in selected models of human breast cancer. By in vitro bioscreens in the context of preclinical studies, we have focused on their ability to inhibit breast cancer cell proliferation by the activation of the intrinsic apoptotic pathway, possibly via mitochondrial perturbations involving Bcl-2 family members and predisposing to programmed cell death. In addition, the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation by metal-based chemotherapeutics is a challenging, yet very promising strategy for targeted therapy development in aggressive cancer diseases, such as triple-negative breast cancer with limited treatment options. These outcomes provide valuable, original knowledge on ruthenium-based candidate drugs and new insights for future optimized cancer treatment protocols.

MicroRNA-125a-5p Is a Downstream Effector of Sorafenib in Its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells.

Abstract: Sorafenib is an antitumor drug for treatment of advanced hepatocellular carcinoma (HCC). It acts as a multikinase inhibitor suppressing cell proliferation and angiogenesis. Human microRNA-125a-5p (miR-125a) is endowed with similar activities and is frequently downregulated in HCC. Looking for a potential microRNA-based mechanism of action of the drug, we found that sorafenib increases cellular expression of miR-125a in cultured HuH-7 and HepG2 HCC cells. Upregulation of the microRNA inhibited cell proliferation by suppression of sirtuin-7, a NAD(+)-dependent deacetylase, and p21/p27-dependent cell cycle arrest in G1. Later, recruitment of miR-125a in the antiproliferative activity of sorafenib was inquired by modulating its expression in combination with the drug treatment. This analysis showed that intracellular delivery of miR-125a had no additive effect on the antiproliferative activity of sorafenib, whereas a miR-125a inhibitor could counteract it. Finally, evaluation of other oncogenic targets of miR-125a revealed its ability to interfere with the expression of matrix metalloproteinase-11, Zbtb7a proto-oncogene, and c-Raf, possibly contributing to the antiproliferative activity of the drug. J. Cell. Physiol. 232: 1907-1913, 2017. © 2016 Wiley Periodicals, Inc.

Metabolic syndrome, endocrine disruptors and prostate cancer associations: biochemical and pathophysiological evidences.

Abstract: // Vincenzo Quagliariello 1,2,3,16 , Sabrina Rossetti 1,2 , Carla Cavaliere 1,4 , Rossella Di Palo 1,5 , Elvira Lamantia 1,6 , Luigi Castaldo 1,7 , Flavia Nocerino 8 , Gianluca Ametrano 1,5 , Francesca Cappuccio 1,9 , Gabriella Malzone 1,6 , Micaela Montanari 1,10 , Daniela Vanacore 1 , Francesco Jacopo Romano 1 , Raffaele Piscitelli 1,11 , Gelsomina Iovane 2 , Maria Filomena Pepe 1,6 , Massimiliano Berretta 12,16 , Carmine D’Aniello 1,13 , Sisto Perdona 7 , Paolo Muto 5 , Gerardo Botti 6 , Gennaro Ciliberto 14,17 , Bianca Maria Veneziani 10 , Francesco De Falco 9 , Piera Maiolino 11 , Michele Caraglia 15 , Maurizio Montella 8 , Rosario Vincenzo Iaffaioli 3,16 and Gaetano Facchini 1,2,16 1 Progetto ONCONET2.0 - Linea progettuale 14 per l’implementazione della prevenzione e diagnosi precoce del tumore alla prostata e testicolo, Regione Campania, Italy 2 Division of Medical Oncology, Department of Uro-Gynaecological Oncology , Istituto Nazionale Tumori ‘Fondazione G. Pascale’ - IRCCS, Naples, Italy 3 Medical Oncology, Abdominal Department, National Cancer Institute G. Pascale Foundation, Napoli, Italy 4 Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto, Taranto, Italy 5 Radiation Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ - IRCCS, Napoli, Italy 6 Pathology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, Naples, Italy 7 Division of Urology, Department of Uro-Gynaecological Oncology , Istituto Nazionale Tumori ‘Fondazione G. Pascale’ - IRCCS, Naples, Italy 8 Epidemiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ - IRCCS, Napoli, Italy 9 Psicology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ - IRCCS, Napoli, Italy 10 Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy 11 Pharmacy Unit, Istituto Nazionale Tumori, Istituto Nazionale Tumori-Fondazione G. Pascale, Naples, Italy 12 Department of Medical Oncology, CRO Aviano, National Cancer Institute, Aviano, Italy 13 Division of Medical Oncology, A.O.R.N. dei COLLI “Ospedali Monaldi-Cotugno-CTO”, Napoli, Italy 14 Scientific Directorate, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ - IRCCS, Napoli, Italy 15 Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy 16 Association for Multidisciplinary Studies in Oncology and Mediterranean Diet, Piazza Nicola Amore, Naples, Italy 17 Scientific Directorate, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Regina Elena’ - IRCCS, Roma, Italy Correspondence to: Vincenzo Quagliariello, email: // Keywords : metabolic syndrome, endocrine disruptors, prostate, cancer, nutrition Received : October 28, 2016 Accepted : February 06, 2017 Published : March 30, 2017 Abstract This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the world’s leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.

Evidence of novel miR-34a-based therapeutic approaches for multiple myeloma treatment.

Abstract: MiR-34a acts as tumor suppressor microRNA (miRNA) in several cancers, including multiple myeloma (MM), by controlling the expression of target proteins involved in cell cycle, differentiation and apoptosis. Here, we have investigated the combination between miR-34a and γ-secretase inhibitor (γSI), Sirtinol or zoledronic acid (ZOL) in order to enhance the inhibitory action of this miRNA on its canonical targets such as Notch1 and SIRT1, and on Ras/MAPK-dependent pathways. Our data demonstrate that miR-34a synthetic mimics significantly enhance the anti-tumor activity of all the above-mentioned anti-cancer agents in RPMI 8226 MM cells. We found that γSI enhanced miR-34a-dependent anti-tumor effects by activating the extrinsic apoptotic pathway which could overcome the cytoprotective autophagic mechanism. Moreover, the combination between miR-34a and γSI increased the cell surface calreticulin (CRT) expression, that is well known for triggering anti-tumor immunological response. The combination between miR-34a and Sirtinol induced the activation of an intrinsic apoptotic pathway along with increased surface expression of CRT. Regarding ZOL, we found a powerful growth inhibition after enforced miR-34a expression, which was not likely attributable to neither apoptosis nor autophagy modulation. Based on our data, the combination of miR-34a with other anti-cancer agents appears a promising anti-MM strategy deserving further investigation.

Regulatory T Cells and Their Prognostic Relevance in Hematologic Malignancies

Abstract: Regulatory T cells (Tregs) have a fundamental function in monitoring the immune homeostasis in healthy individuals. In cancer and, in particular, in hematological malignancies, Tregs exert a major immunosuppressive activity, thus playing a critical role in tumor cell growth, proliferation, and survival. Here, we summarize published data on the prognostic significance of Tregs in hematological malignancies and show that they are highly conflicting. The heterogeneity of the experimental approaches that were used explains-at least in part-the discordant results reported by different groups that have investigated the role of Tregs in cancer. In fact, different tissues have been studied (i.e., peripheral blood, bone marrow, and lymph node), applying different methods (i.e., flow cytometry versus immunohistochemistry, whole blood versus isolated peripheral blood mononuclear cells versus depletion of CD25+ cells, various panels of monoclonal antibodies, techniques of fixation and permeabilization, and gating strategies). This is of relevance in order to stress the need to apply standardized approaches in the study of Tregs in hematological malignancies and in cancer in general.

Epigenetic changes induced by green tea catechins are associated with prostate cancer

Abstract: Prostate cancer is one of the most difficult cancers to treat especially when it becomes hormone resistant such as castrate resistant prostate cancer (CRPC) and subsequent metastatic CRPC. Apart from the genetic alterations in prostate cancer, epigenetic modifications also play an important role in the development and neoplastic progression of this disease. These include DNA methylation, histone modifications, and non-coding microRNAs. miRNAs are a novel class of small endogenous single-stranded non-coding RNAs of 19-25 nucleotides in length that typically silence gene expression. Considering the reversibility of epigenetic alterations in early carcinogenesis process, reversion (correction) of these modifications by green tea catechins could be a promising strategy for cancer chemoprevention and therapy. Recent evidence suggests that green tea catechins such as epigallocatechin gallate (EGCG) not only act as epigenetic modulators but can also modify miRNA expression and their target mRNAs, consistently contributing to the inhibition of prostate carcinogenesis. Various studies also indicate that several green tea polyphenols (GTPs) exert synergistic effects with other cancer chemotherapeutic agents. Therefore, the use of appropriate combinations of green tea catechins with the existing chemotherapeutics will lead to a reduction in side effects without decreasing the chemotherapeutic effects. This review will summarize the key results from recent studies detailing the effects of green tea catechins such as EGCG on epigenetic alterations and miRNA expression in prostate cancer.

Radiotherapy prolongs the survival of advanced non-small-cell lung cancer patients undergone to an immune-modulating treatment with dose-fractioned cisplatin and metronomic etoposide and bevacizumab (mPEBev)

Abstract: // Pierpaolo Pastina 1 , Valerio Nardone 1 , Cirino Botta 2 , Stefania Croci 1 , Paolo Tini 1 , Giuseppe Battaglia 1 , Veronica Ricci 3 , Maria Grazia Cusi 4 , Claudia Gandolfo 4 , Gabriella Misso 5 , Silvia Zappavigna 5 , Michele Caraglia 5,6 , Antonio Giordano 6,7 , Donatella Aldinucci 8 , Pierfrancesco Tassone 2,6 , Pierosandro Tagliaferri 2 , Luigi Pirtoli 1 and Pierpaolo Correale 1,9 1 Radiotherapy Unit, Department of Medicine, Surgery, and Neuroscience, Siena University Hospital, Siena, Italy 2 Medical Oncology Unit, AUO “Mater Domini”, “Magna Graecia” University, Catanzaro, Italy 3 Radiology Unit,Department of Medicine, Surgery, and Neuroscience, Siena University Hospital, Siena, Italy 4 Department of Medical Biotechnology, Microbiology and Virology Unit, University of Siena, Siena, Italy 5 Department of Biochemistry, Biophysics and General Pathology, University of Campania “L. Vanvitelli”, Naples, Italy 6 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA 7 Department of Medicine, Surgery, and Neuroscience, University of Siena and Istituto Toscano Tumori (ITT), Siena, Italy 8 Department of Experimental Oncology 2, CRO Aviano National Cancer Institute, Aviano, Italy 9 Medical Oncology Unit, Metropolitan Hospital “Bianchi-Melacrino-Morelli, Reggio Calabria, Italy Correspondence to: Pierpaolo Correale, email: // Michele Caraglia, email: // Keywords : immune-modulation, radiation therapy, metronomic chemotherapy, NSCLC, retrospective analysis Received : March 21, 2017 Accepted : June 20, 2017 Published : August 24, 2017 Abstract Radiotherapy (RT), together with a direct cytolytic effect on tumor tissue, also elicits systemic immunological events, which sometimes result in the regression of distant metastases (abscopal effect). We have shown the safety and anti-tumor activity of a novel metronomic chemotherapy (mCH) regimen with dose-fractioned cisplatin, oral etoposide and bevacizumab, a mAb against the vasculo-endothelial-growth-factor (mPEBev regimen), in metastatic non-small-cell-lung cancer (mNSCLC). This regimen, designed on the results of translational studies, showed immune-modulating effects that could trigger and empower the immunological effects associated with tumor irradiation. In order to assess this, we carried out a retrospective analysis in a subset of 69 consecutive patients who received the mPEBev regimen within the BEVA2007 trial. Forty-five of these patients, also received palliative RT of one or more metastatic sites. Statistical analysis (a Log-rank test) revealed a much longer median survival in the group of patients who received RT [mCH vs mCH + RT: 12.1 +/-2.5 (95%CI 3.35-8.6) vs 22.12 +/-4.3 (95%CI 11.9-26.087) months; P =0.015] with no difference in progression-free survival. In particular, their survival correlated with the mPEBev regimen ability to induce the percentage of activated dendritic cells (DCs) (CD3-CD11b+CD15-CD83+CD80+) [Fold to baseline value (FBV) ≤1 vs >1: 4+/-5.389 (95%CI,0- 14.56) vs 56+/-23.05 (95%CI,10.8-101.2) months; P :0.049)] and central-memory- T-cells (CD3+CD8+CD45RA-CCR7+) [FBV ≤ 1 vs >1: 8+/-5.96 (95%CI,0-19.68) vs 31+/-12.3 (95%CI,6.94-55.1) months; P :0.045]. These results suggest that tumor irradiation may prolong the survival of NSCLC patients undergone mPEBev regimen presumably by eliciting an immune-mediated effect and provide the rationale for further perspective clinical studies.

Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells

Abstract: // Cinzia Borghese 1, * , Naike Casagrande 1, * , Eliana Pivetta 1 , Alfonso Colombatti 1 , Mariarosaria Boccellino 2, 3 , Evzen Amler 4, 5 , Nicola Normanno 6 , Michele Caraglia 2, 3 , Giuseppe De Rosa 7 and Donatella Aldinucci 1 1 Molecular Oncology Unit, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN, Italy 2 Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy 3 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA 4 Indoor Environmental Quality, University Center for Energy Efficient Buildings, Czech Technical University in Prague, Bustěhrad, Czech Republic 5 Laboratory of Tissue Engineering, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czech Republic 6 Cell Biology & Biotherapy Unit, Istituto Nazionale Tumori “Fondazione G Pascale”-IRCCS, Naples, Italy 7 Department of Pharmacy, Federico II University of Naples, Naples, Italy * These authors have contributed equally to this work Correspondence to: Donatella Aldinucci, email: daldinucci@cro.it Keywords: zoledronic acid, self-assembling nanoparticles, mesenchymal stromal cells, prostate cancer, tumor microenvironment Received: January 21, 2017 Accepted: March 22, 2017 Published: April 19, 2017 ABSTRACT Zoledronic Acid (ZA) rapidly concentrates into the bone and reduces skeletal-related events and pain in bone metastatic prostate cancer (PCa), but exerts only a limited or absent impact as anti-cancer activity. Recently, we developed self-assembling nanoparticles (NPS) encapsulating zoledronic acid (NZ) that allowed a higher intratumor delivery of the drug compared with free zoledronic acid (ZA) in in vivo cancer models of PCa. Increasing evidence suggests that Bone Marrow (BM) Mesenchymal stromal cells (BM-MSCs) are recruited into the stroma of developing tumors where they contribute to progression by enhancing tumor growth and metastasis. We demonstrated that treatment with NZ decreased migration and differentiation into adipocytes and osteoblasts of MSCs and inhibited osteoclastogenesis. Treatment with NZ reduced the capability of MSCs to promote the migration and the clonogenic growth of the prostate cancer cell lines PC3 and DU145. The levels of Interleukin-6 and of the pro-angiogenic factors VEGF and FGF-2 were significantly reduced in MSC-CM derived from MSCs treated with NZ, and CCL5 secretion was almost totally abolished. Moreover, treatment of MSCs with supernatants from PC3 cells, leading to tumor-educated MSCs (TE-MSCs), increased the secretion of IL-6, CCL5, VEGF and FGF-2 by MSCs and increased their capability to increase PC3 cells clonogenic growth. Treatment with NZ decreased cytokine secretion and the pro-tumorigenic effects also of TE-MSCS. In conclusion, demonstrating that NZ is capable to inhibit the cross talk between MSCs and PCa, this study provides a novel insight to explain the powerful anticancer activity of NZ on PCa.

Urotensin-II Receptor: A Double Identity Receptor Involved in Vasoconstriction and in the Development of Digestive Tract Cancers and other Tumors

Abstract: Urotensin II and Urotensin-II receptors are important molecular factors that regulate vasoconstriction and all the diseases that are linked to abnormalities in blood pressure regulation (i.e.: hypertension, kidney diseases, cirrhosis etc.). Recently, Urotensin II and its receptor have also been involved in metabolic syndrome, diabetes and schizophrenia. Recent strong findings suggest that Urotensin II and its receptor are involved in the onset and development of different epithelial cancers. Indeed, it was reported that cell growth, motility and invasion in human breast, bladder, prostate, colorectal and glioblastoma cancer cells were regulated by Urotensin II and Urotensin-II receptor axis. This axis also regulated focal adhesion kinase and small Guanosine-5'-triphosphate binding proteins that likely had a role in motility and invasion mediated by Urotensin-II receptor. Additionally, its expression on tumour tissues is variably associated to the prediction of the clinical outcome of the patients and it can be considered an alternative molecular marker to be used as prognostic factor in human cancers. In conclusion, a new weapon in the treatment of human cancers is highlighting a new scenario for the future.

Aggressiveness pattern and second primary tumor risk associated with basaloid squamous cell carcinoma of the larynx.

Abstract: // Filippo Ricciardiello 1 , Michele Caraglia 3 , Brigida Iorio 2 , Teresa Abate 1 , Mariarosaria Boccellino 3 , Giuseppe Colella 4 , Flavia Oliva 1 , Pierpaolo Ferrise 1 , Silvia Zappavigna 3 , Mario Faenza 4 , Giuseppe A. Ferraro 4 , Giulio Sequino 1 , Giovanni Francesco Nicoletti 4 and Massimo Mesolella 2 1 Division of Otolaryngology, “A. Cardarelli” Hospital, Naples, Italy 2 Department of Neurological, Reproductive and Odontostomatological Sciences, University “Federico II” of Naples, Naples, Italy 3 Department of Biochemistry, Biophysics and General Pathology, University of Campania “L. Vanvitelli”, Naples, Italy 4 Department of Medical, Surgical and Dental Specialties, University of Campania “L. Vanvitelli”, Naples, Italy Correspondence to: Michele Caraglia, email: michele.caraglia@unina2.it , michele.caraglia@fastwebnet.it Keywords: laryngea lbasaloid squamocellular carcinoma (BSCC); prognosis of laryngeal basaloid squamous cell carcinoma; mortality of laryngeal BSCC; loco-regional recurrence in laryngeal BSCC Received: July 26, 2017 Accepted: August 23, 2017 Published: September 28, 2017 ABSTRACT Basaloid squamous cell carcinoma (BSCC) is a rare, aggressive and distinct variant of squamous cell carcinoma (SCC) of the upper respiratory and digestive tract. We have evaluated disease specific survival (DSS) and overall survival (OS) through Kaplan-Meier method and mortality risk through univariate statistical analysis of Cox in 42 cases of BSCC and other 42 of laryngeal SCC (LSCC) matched for both age and sex. We demonstrated that laryngeal BSCC is a more aggressive tumor than LSCC as is associated to higher nodal recurrence of pathology ( 5 vs 2 patients, overall risk, OR 2.7), a reduced survival (median survival 34 vs 40 months, OR 3.2 for mortality); in addition, basaloid patients have a higher risk to be affected by second primary tumors (13 vs 3 patients, OR 5.8) and a higher probability to die for this second tumor (Hazard Risk, HR 4.4). The analysis of survival shows an increased mortality risk concurrent with the parameters assessed by univariate analyses that assume a predictive and statistical significance in second tumor and grading in basaloid LSSC.

Anti-cancer activity of dose-fractioned mPE +/- bevacizumab regimen is paralleled by immune-modulation in advanced squamous NSLC patients.

Abstract: Background: Results from the BEVA2007 trial, suggest that the metronomic chemotherapy regimen with dose-fractioned cisplatin and oral etoposide (mPE) +/− bevacizumab, a monoclonal antibody to the vascular endothelial growth factor (VEGF), shows anti-angiogenic and immunological effects and is a safe and active treatment for metastatic non-small cell lung cancer (mNSCLC) patients. We carried out a retrospective analysis aimed to evaluate the antitumor effects of this treatment in a subset of patients with squamous histology. Methods: Retrospective analysis was carried out in a subset of 31 patients with squamous histology enrolled in the study between September 2007 and September 2015. All of the patients received chemotherapy with cisplatin (30 mg/sqm, days 1–3q21) and oral etoposide (50 mg, days 1–15q21) (mPE) and 14 of them also received bevacizumab 5 mg/kg on the day 3q21 (mPEBev regimen). Results: This treatment showed a disease control rate of 71% with a mean progression free survival (PFS) and overall survival (OS) of 13.6 and 17 months respectively. After 4 treatment courses, 6 patients showing a remarkable tumor shrinkage, underwent to radical surgery, attaining a significant advantage in term of survival (P=0.04). Kaplan-Meier and log-rank test identified the longest survival in patients presenting low baseline levels in neutrophil-to-lymphocyte ratio (NLR) (P=0.05), interleukin (IL) 17A (P=0.036), regulatory-T-cells (T reg s) (P=0.020), and activated CD83+ dendritic cells (DCs) (P=0.03). Conclusions: These results suggest that the mPE +/− bevacizumab regimen is feasible and should be tested in comparative trials in advanced squamous-NSCLC (sqNSCLC). Moreover, its immune-biological effects strongly suggest the investigation in sequential combinations with immune check-point inhibitors.

Measurement of Autophagy by Flow Cytometry.

Abstract: Autophagy activation is characterized by the accumulation of double-membrane autophagic vesicles (autophagosomes) in the cytoplasm. The mere presence of autophagosomes in the cytoplasm does not necessarily indicate an increased level of autophagy, since the blockade of any step downstream of autophagosome formation increases the number of autophagosomes. Therefore, quantitative methods for the detection of cytoplasmic protein turnover should be employed in addition to autophagosome monitoring, to verify increased levels of autophagy. At the present, multiple methods are available for the quantification of autophagy and the identification of autophagosomes. Here, we detail the in vitro methods currently available to detect autophagic cell death by flow cytometry analysis.

A miRNA signature suggestive of nodal metastases from laryngeal carcinoma

Abstract: The discovery that miRNAs are frequently deregulated in tumours offers the opportunity to identify them as prognostic and diagnostic markers. The aim of this multicentric study is to identify a miRNA expression profile specific for laryngeal cancer. The secondary endpoint was to identify specific deregulated miRNAs with potential as prognostic biomarkers for tumour spread and nodal involvement, and specifically to search for a miRNA pattern pathognomonic for N+ laryngeal cancer and for N- tissues. We identified 20 miRNAs specific for laryngeal cancer and a tissue-specific miRNA signature that is predictive of lymph node metastases in laryngeal carcinoma characterised by 11 miRNAs, seven of which are overexpressed (upregulated) and four downregulated. These results allow the identification of a group of potential specific tumour biomarkers for laryngeal carcinoma that can be used to improve its diagnosis, particularly in early stages, as well as its prognosis.

A Long-term Treatment with Silybin in Patients with Non-alcoholic Steatohepatitis Stimulates Catalase Activity in Human Endothelial Cells.

Abstract: Aim To compare levels of oxidative stress markers in patients' sera with non-alcoholic steatohepatitis (NASH) treated for 12 months (T12) with silybin conjugated with phosphatidylcholine (Realsil®) (R) or placebo (P) and investigate oxidative stress responses in human endothelial cells conditioned with patients' sera. Patients and methods We recruited twenty-seven patients with histological NASH. We measured thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase (CAT) activities in human endothelial cells conditioned with patients' sera exposed or not to H2O2 Results: We found in decreased-TBARS patients' sera, at T12, a decrease of alanine aminotransferase (p=0.038), transforming growth factor-beta (p=0.009) and procollagen I (p=0.001). By dividing patients into two groups, increased (P-I/R-I) and decreased TBARS (P-II/R-II) at T12 compared to T0, we found an increased CAT activity in conditioned endothelial cells at T12 in both groups (p=0.05 and p=0.001, respectively). Conclusion Realsil® may be effective against endothelial dysfunction by stimulating the cellular antioxidant defense.

Optimal Management of Prostate Cancer Based on its Natural Clinical History

Abstract: Prostate cancer is the most common malignancy in males and, despite a marked improvement in diagnostic techniques, a not small percentage of prostate tumours is still diagnosed in advanced stage. It is now clear that prostate cancer passes through distinct phases during its natural history, starting from an initial phase, in which the disease has a locoregional extent, until a very late phase when it becomes refractory to hormone therapy. It is important to distinguish between local disease, in which tumor may be considered localized in the gland and a systemic disease characterized by high tumor burden and/or dissemination of circulating tumour cells. All the prostate cancers, at first diagnosis, are characterized by high sensitivity to the androgen deprivation therapy (ADT); however, during the natural history, after a variable period, they become castration resistant. In the past, few therapy options were available for castration resistant prostate cancer, while at present much more approaches can be employed, both hormone-based therapies and chemotherapy regimens. Hypercastration agents are defined as drugs capable to target the androgenandrogen receptor axis even in castrate resistant conditions. Abiraterone and enzalutamide are the only two hypercastration agents available for clinical use. Osteoclast targeted agents, such as zoledronic acid and denosumab can always been employed, but their use should be limited to the castrate resistant setting. The optimal understanding of all phases characterizing the natural history of prostate cancer may certainly be useful for the selection of the best therapeutic options in prostate cancer.

Tissue transglutaminase (TG2) is involved in the resistance of cancer cells to the histone deacetylase (HDAC) inhibitor vorinostat.

Abstract: Vorinostat demonstrated preclinical and clinical efficacy in human cancers and is the first histone deacetylase inhibitor (HDACi) approved for cancer treatment. Tissue transglutaminase (TG2) is a multifunctional enzyme that catalyzes a Ca2+ dependent transamidating reaction resulting in covalent cross-links between proteins. TG2 acts also as G-protein in trans-membrane signaling and as a cell surface adhesion mediator. TG2 up-regulation has been demonstrated in several cancers and its expression levels correlate with resistance to chemotherapy and metastatic potential. We demonstrated that the anti-proliferative effect of the HDACi vorinostat is paralleled by the induction of TG2 mRNA and protein expression in cancer cells but not in ex vivo treated peripheral blood lymphocytes. This effect was also shared by other pan-HDACi and resulted in increased TG2 transamidating activity. Notably, high TG2 basal levels in a panel of cancer cell lines correlated with lower vorinostat antiproliferative activity. Notably, in TG2-knockdown cancer cells vorinostat anti-proliferative and pro-apoptotic effects were enhanced, whereas in TG2-full-length transfected cells were impaired, suggesting that TG2 could represent a mechanism of intrinsic or acquired resistance to vorinostat. In fact, co-treatment of tumor cells with inhibitors of TG2 transamidating activity potentiated the antitumor effect of vorinostat. Moreover, vorinostat-resistant MCF7 cells selected by stepwise increasing concentrations of the drug, significantly overexpressed TG2 protein compared to parental cells, and co-treatment of these cells with TG2 inhibitors reversed vorinostat-resistance. Taken together, our data demonstrated that TG2 is involved in the resistance of cancer cells to vorinostat, as well as to other HDACi.

Impact of curcumin on the regulation of microRNAs in colorectal cancer.

Abstract: Colorectal cancer is the third leading cause of cancer-related death in both men and women [1], and approximately 1 million new cases and 500,000 deaths per year are reported in Western countries [2]. Moreover, the 5-year survival in patients with advanced stages of colon cancer is lower than 8% and its recurrence is about 50% even after tumor resection surgery and chemotherapy [2]. Hence, there is an important need for early diagnosis using molecular biomarkers, and novel treatments to help more effective chemotherapy for colorectal cancer management are warranted.

Antitumor activity of interferon-β1a in hormone refractory prostate cancer with neuroendocrine differentiation

Abstract: Type I interferons (IFN-α and IFN-β) are a class of cytokines that exert several biological activities, such as modulation of cell proliferation and differentiation and of the immune system. Although these cytokines interact with a common receptor complex, IFN-β showed a more potent antitumor activity than IFN-α in several tumor models. New recombinant human IFN-β products, such as IFN-β1a and IFN-β1b, have been produced in order to improve the stability and bioavailability of natural IFN-β. In this report, we analyzed the effects of recombinant IFN-β1a on the cell proliferation of two human androgen-resistant prostate cancer cell lines with neuroendocrine differentiation (DU-145, PC-3) and related mechanisms of action. The effects of IFN-β1a on the cell growth proliferation, cell cycle, and apoptosis have been evaluated in DU-145 and PC-3 cells through MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. Moreover, the expression of neuron-specific enolase (NSE), cleaved caspase-3, caspase-8, and PARP was evaluated through Western blotting. IFN-β1a showed a significant anti-proliferative activity in both androgen-resistant cell lines. This effect was related to cell cycle perturbation and induction in apoptosis, as shown by flow cytometric analysis, the activation of caspase-3 and caspase-8 and PARP cleavage during incubation with IFN-β1a. Moreover, this cytokine reduced the expression of NSE in both cell lines. Recombinant IFN-β1a (Rebif) showed a potent in vitro anti-proliferative activity in androgen-resistant prostate cancer cells, and it could represent a promising tool for the treatment of this tumor.

Peptide Functionalization of Silicon for Detection and Classification of Prostatic Cells

Abstract: The development of simple, rapid, and low cost methods for early detection, identification, and measurement of multiple biomarkers remains a challenge to improve diagnosis, treatment monitoring, and prognosis of cancer. Biosensing technology, combining the properties of biological systems with functional advanced materials, guarantees rapid, reproducible, and highly sensitive cell detection. In this study, we developed silicon-based biochips for prostate cancer PC3 cells detection by using cytokeratin 8/18 and Urotensin Receptor (UTR) as markers in order to obtain a biochip-based diagnostic system. Spectroscopic ellipsometry and fluorescence microscopy were used to characterize surface homogeneity and chemical properties. Cell detection was investigated by optical microscopy. Moreover, synthetic fluorescently labeled peptides were prepared and used for developing faster and lower-cost identification assay compared with classic ELISA immunoassay. Results showed an effective immobilization of PC3 cells on silicon surface and the specific recognition of these cells by fluorescent Urotensin II (4–11). In conclusion, this strategy could be really useful as diagnostic system for prostate cancer.

Melanoma Adjuvant Treatment: Current Insight and Clinical Features

Abstract: Melanoma represents 2-3% of all cancers, 95% of them arise from skin, while only 5% are non-cutaneous melanoma. Despite an optimal surgery management, the risk of a local and systemic relapse remains high, particularly in high-risk patients (node-positive or node-negative T3b, T4 a/b). We conducted a systematic review of the main published and ongoing phase I/II/III trials between 2000 and June 2015 on the adjuvant treatment of cutaneous melanoma. The IFN remains the only option currently available for this aim. Ipilimumab represents a possible breakthrough in this setting, considering the positive results of the EORTC 18701 trials in terms of disease free survival (DFS), while data regarding OS are pending. Recent advances in the understanding of the biology of melanoma result in the identification of MAPK pathway role in the melanoma development. Based on these features, B-RAF inhibitors and their combination with immunotherapy could represent the upcoming therapeutic strategy.

Early detection of laryngeal cancer: prominence of miRNA signature as a new tool for clinicians

Abstract: Early detection of laryngeal cancer, essential in the initial stages of the disease to achieve a high survival rate, is unfortunately hampered by the lack of specific symptoms. In this regard, there is a pressing need to dispose of reliable and non-invasive diagnostic and prognostic markers for a real time monitoring availing of accurate and reproducible methods, in order ensure applicability for early diagnosis and primary and secondary prevention. This review focuses on the recent reports that emphasize the crucial role of miRNAs in regulating laryngeal cancer tumorigenesis. In detail, we have reported the most characterized miRNAs with an established oncogenic or oncosuppressive role in cell biology of laryngeal cancer, also describing, for each of them, the main molecular mechanisms responsible for their specific function. We have also defined the potential of miRNAs as novel diagnostic and prognostic markers in virtue of their differential expression between laryngeal carcinoma tissues and the adjacent normal counterpart. Moreover, their proven stability in systemic circulation and other body fluids, as well as their easy detection and quantization, makes the analysis of miRNA signatures an excellent tool for clinicians as hallmark for cancer classification and diagnosis. Moreover, an eventual similarity between deregulated miRNAs in tumor tissues and in body fluids would allow to provide a considerable advantage for patients’ compliance, replacing invasive tissue biopsies with simple assays on easily obtained blood products.

Stealth liposomes for the delivery of zoledronic acid into tumors enhance the anticancer activity of the drug

Abstract: Zoledronic acid (ZOL) is a third generation aminobisphosphonate, commonly used for the treatment of bone metastases. Several studies have shown a direct in vitro antitumor activity of ZOL but a clear evidence of clinical activity is still lacking. Unfortunately, the use of ZOL as an anticancer agent in extraskeletal tissues is limited probably because it is rapidly removed from the blood and tends to accumulate in the bone. On these bases, we developed stealth liposomes encapsulating ZOL (Lipo- ZOL) to improve the pharmacokinetic profile of the drug. Compared to free ZOL, Lipo-ZOL induced a stronger inhibition of growth in two different cancer cell lines H460 and CG5. Moreover, Lipo-ZOL also significantly caused a larger inhibition of tumor growth and increased the overall survival in murine models of human lung and breast cancer, in comparison with free ZOL. These results suggest the use of Lipo-ZOL as a potential anticancer agent in patients with neoplastic disease.

The Role of Target Therapy in the Treatment of Gastrointestinal Noncolorectal Cancers: Clinical Impact and Cost Consideration.

Abstract: Gastrointestinal (GI) tumors are among the leading cause of death in cancer patients worldwide. Particularly, gastric cancer (GC) is the third cause of cancer deaths, whereas esophageal neoplasm is the eighth leading most common cancer worldwide and its incidence, especially adenocarcinoma type, is continuously increasing. Also, Hepatocellular carcinoma, Cholangiocarcinoma and pancreatic cancer represent a very interesting model to multidisciplinary approach and recently new drugs are used in their treatment. Currently, new clinical trials are designed including classic chemotherapy in association with either small molecule inhibitors (i.e. Tyrosine Kinase inhibitors) and/or monoclonal antibody (i.e. anti-EGFR antibody). Moreover, a comprehensive list of new molecules for target therapy is included in this issue. The development of new treatment modalities (multidisciplinary approach) and targeted therapy approaches have contributed to improving the outcome in these cancer diseases. During the past few years, remarkable progress in molecular biology of malignancy, the discovery of specific targets, and the resulting development of systemic drugs that block critical kinases and several molecular pathways have all contributed to progress in cancer treatment, also in GI non-colorectal cancer treatment.