113 results on '"Romano, Maria"'
Search Results
2. Abstract 586: Ionizing radiation-induced PD-L1 upregulation in glioma: a crucial role for the molecular chaperone FKBP5
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D'ARRIGO, PAOLO, RUSSO, MICHELE, GUADAGNO, ELIA, PACELLI, ROBERTO, STAIBANO, STEFANIA, ILARDI, GENNARO, ROMANO, MARIA FIAMMETTA, DEL BASSO DE CARO, MARIALAURA, ROMANO, SIMONA, Del Basso De Caro, Marialaura, Rea, Anna, Tufano, Martina, D'Arrigo, Paolo, Russo, Michele, Guadagno, Elia, Pacelli, Roberto, Del Basso De Caro, Marialaura, Rea, Anna, Tufano, Martina, Staibano, Stefania, Ilardi, Gennaro, Romano, MARIA FIAMMETTA, DEL BASSO DE CARO, Marialaura, and Romano, Simona
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Gene isoform ,Cancer Research ,Glycosylation ,Immunoprecipitation ,Golgi apparatus ,medicine.disease ,Molecular biology ,Cell biology ,symbols.namesake ,chemistry.chemical_compound ,Oncology ,Downregulation and upregulation ,Membrane protein ,chemistry ,Glioma ,medicine ,symbols ,Glioma, FKBP51, PD-L1 ,Cell fractionation - Abstract
Glioblastoma can avoid immune surveillance and induce tumor tolerance, through inhibitory molecules, e.g. PD-L1. Ionizing radiation (IR), used to treat this tumor, is known to increase tumor expression of PD-L1, thus inducing resistance mechanisms. Finding molecular determinants involved in IR-induced PD-L1 may provide a target for preventing such an effect and improve radiotherapy outcomes. We demonstrated that the short isoform of the cochaperone FKBP51 (FKBP51s) regulated PD-L1 expression in melanoma. In glioma, FKBP51s was expressed at high levels, together with PD-L1 and its silencing reduced PD-L1 levels. Conversely, overexpression of FKBP51s increased PD-L1. Different PD-L1 isoforms were observed by immunoblot. A lower band (~37 kDa) corresponding to the naïve protein and two upper bands (~50, ~68 kDa) ascribable to post-translationally modified isoforms. FKBP51s was found mainly bound to the heaviest bands of PD-L1, reasonably mature protein, while the canonical isoform FKBP51 appeared to bind only the naïve protein. Mature PD-L1 protein consists in carbohydrates addition, the principal chemical modification to most plasma membrane proteins, and, particularly, N-glycosylation. Treatment of immunoprecipitated PD-L1 protein with PNGaseF produced a decrease of the highest band and the appearance of a lower band, corresponding to the naïve PD-L1, in accordance with the concept that the heaviest band of PD-L1 is a glycosylated form. Moreover, following subcellular fractionation to obtain extracts from ER and Golgi compartments, we found that naïve 37 kDa PD-L1 was detectable in the ER, but not in the Golgi. The PD-L1 glycosylated band was expressed in ER in a small proportion and mostly in the Golgi. FKBP51s, but not the canonical FKBP51, was found in ER. Co-IP of FKBP51s and PD-L1 from ER extract confirmed the two proteins interacted each other in ER. Our results show that naïve PD-L1 colocalized in the ER of glioma cell complexed with FKBP51s, while the PD-L1 glycosylated form was measured in the Golgi apparatus. Treatment of glioma cell with increasing doses of IR upregulated PD-L1 expression, in a dose-response manner. Particularly, we found a significant increase in PD-L1 expression at 4 and 8 Gy, in comparison with unirradiated glioma cell. Moreover, IR induction of mature PD-L1 was efficiently counteracted by FKBP51s silencing. Subcellular fractionation of glioma cell subjected to IR in kinetics showed an early and transitory decrease in FKBP51s ER levels at 3hrs, in line with a reduction of the glycosylated band in the whole lysate. After 8 hrs from IR, FKBP51s rose up again in the ER inducing a full maturation of PD-L1. These findings suggested that FKBP51s has a role in catalyzing PD-L1 folding, an essential step to glycosylation, through which it controls the affinity for PD1. This study identifies FKBP51s as an essential element that regulates PD-L1 expression on glioma cell, which is exploited by the tumor to resist to IR. Citation Format: Paolo D'Arrigo, Michele Russo, Elia Guadagno, Roberto Pacelli, Maria Laura Del Basso De caro, Anna Rea, Martina Tufano, Stefania Staibano, Gennaro Ilardi, Maria Fiammetta Romano, Simona Romano. Ionizing radiation-induced PD-L1 upregulation in glioma: a crucial role for the molecular chaperone FKBP5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 586. doi:10.1158/1538-7445.AM2017-586
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- 2017
3. Role of electrocardiography and echocardiography in prevention and predicting outcome of subjects at increased risk of heart failure
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Bello, Vitantonio Di, Carrubba, Salvatore La, Antonini-Canterin, Francesco, Salvo, Giovanni Di, Caso, Pio, Canna, Giovanni La, Erlicher, Andrea, Badano, Luigi, Romano, Maria Francesca, Zito, Concetta, Vriz, Olga, Conte, Lorenzo, Carerj, Scipione, Monte, Ines, Bello, V, Carrubba, S, Antonini-Canterin, F, Salvo, G, Caso, P, Canna, G, Erlicher, A, Badano, L, Romano, M, Zito, C, Vriz, O, Conte, L, and Carerj, S
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Cardiovascular risk factors ,echocardiography ,electrocardiography ,heart failure ,Aged ,Echocardiography ,Female ,Heart Failure ,Humans ,Male ,Middle Aged ,Ventricular Dysfunction, Left ,Electrocardiography ,Epidemiology ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Left ,Outcome (game theory) ,Cardiovascular risk factor ,Intervention (counseling) ,Cardiovascular risk factors, echocardiography, electrocardiography, heart failure ,Ventricular Dysfunction ,Medicine ,Systole ,Intensive care medicine ,medicine.diagnostic_test ,business.industry ,Surrogate endpoint ,Medicine (all) ,food and beverages ,medicine.disease ,Increased risk ,Heart failure ,business - Abstract
Background: Asymptomatic left ventricular dysfunction (ALVD) is relatively common in both community and high-risk populations. Early pharmacological intervention can improve clinical outcomes in subjects with this condition. Objectives: This multicentre study consists on electrocardiographic and echocardiographic examination of stage A and B heart failure (HF) asymptomatic subjects with one or more cardiovascular risk factors, to assess the prognostic value of cardiovascular risk factors per se, clinical history, and electrocardiographic and echocardiographic parameters in prediction of progression of HF and/or in development of cardiovascular primary or secondary events. Material and methods: A total of 2142 asymptomatic subjects (mean age 63 years, 1162 males) performed an electrocardiographic and echocardiographic examination. Electrocardiogram (ECG) pathological signs according to Minnesota code and left ventricular dysfunction both systolic and diastolic by echocardiography were evaluated. There were 2002 subjects who were followed up for 26 11 months, observing their primary and secondary end points. Results: At follow up, the study population presented 111 primary end points (5.2%) and 441 secondary end points (20.6%). ECG criteria of LV hypertrophy and signs of ischaemia or previous myocardial infarction (p
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- 2015
4. Web Health Monitoring Survey: A New Approach to Enhance the Effectiveness of Telemedicine Systems
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Romano, Maria Francesca, Sardella, Maria Vittoria, and Alboni, Fabrizio
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Web questionnaire ,Telemedicine ,020205 medical informatics ,Web Health monitoring survey ,telemedicine ,virtual checkup ,survey quality ,quality indicators ,paradata ,media_common.quotation_subject ,02 engineering and technology ,Paradata ,03 medical and health sciences ,Survey methodology ,0302 clinical medicine ,Nursing ,0202 electrical engineering, electronic engineering, information engineering ,medicine ,Quality (business) ,030212 general & internal medicine ,media_common ,Response rate (survey) ,Original Paper ,Data collection ,business.industry ,General Medicine ,medicine.disease ,Focus group ,Information and Communications Technology ,Medical emergency ,business - Abstract
Background: Aging of the European population and interest in a healthy population in western countries have contributed to an increase in the number of health surveys, where the role of survey design, data collection, and data analysis methodology is clear and recognized by the whole scientific community. Survey methodology has had to couple with the challenges deriving from data collection through information and communications technology (ICT). Telemedicine systems have not used patients as a source of information, often limiting them to collecting only biometric data. A more effective telemonitoring system would be able to collect objective and subjective data (biometric parameters and symptoms reported by the patients themselves), and to control the quality of subjective data collected: this goal be achieved only by using and merging competencies from both survey methodology and health research. Objective: The objective of our study was to propose new metrics to control the quality of data, along with the well-known indicators of survey methodology. Web questionnaires administered daily to a group of patients for an extended length of time are a Web health monitoring survey (WHMS) in a telemedicine system. Methods: We calculated indicators based on paradata collected during a WHMS study involving 12 patients, who signed in to the website daily for 2 months. Results: The patients’ involvement was very high: the patients’ response rate ranged between 1.00 and 0.82, with an outlier of 0.65. Item nonresponse rate was very low, ranging between 0.0% and 7.4%. We propose adherence to the chosen time to connect to the website as a measure of involvement and cooperation by the patients: the difference from the median time ranged between 11 and 24 minutes, demonstrating very good cooperation and involvement from all patients. To measure habituation to the questionnaire, we also compared nonresponse rates to the items between the first and the second month of the study, and found no significant difference. We computed the time to complete the questionnaire both as a measure of possible burden for patient, and to detect the risk of automatic responses. Neither of these hypothesis was confirmed, and differences in time to completion seemed to depend on health conditions. Focus groups with patients confirmed their appreciation for this “new” active role in a telemonitoring system. Conclusions: The main and innovative aspect of our proposal is the use of a Web questionnaire to virtually recreate a checkup visit, integrating subjective (patient’s information) with objective data (biometric information). Our results, although preliminary and if need of further study, appear promising in proposing more effective telemedicine systems. Survey methodology could have an effective role in this growing field of research and applications.
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- 2016
5. Correction: Clock Gene Variation Is Associated with Breeding Phenology and Maybe under Directional Selection in the Migratory Barn Swallow
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Caprioli, Manuela, Ambrosini, Roberto, Boncoraglio, Giuseppe, Gatti, Emanuele, Romano, Andrea, Romano, Maria, Rubolini, Diego, Gianfranceschi, Luca, and Saino, Nicola
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Multidisciplinary ,Science ,lcsh:R ,Correction ,lcsh:Medicine ,Medicine ,lcsh:Q ,lcsh:Science - Published
- 2012
6. Defect of CD2- and CD3-mediated activation pathways in T cells of atopic patients: role of interleukin 2
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Maria Fiammetta Romano, Giuliana Valerio, Maria Caterina Turco, Salvatore Venuta, Salvatore Formisano, ROMANO, MARIA FIAMMETTA, SPADARO, GIUSEPPE, Maria Fiammetta, Romano, Giuliana, Valerio, Maria Caterina, Turco, Spadaro, Giuseppe, Salvatore, Venuta, Salvatore, Formisano, and Romano, MARIA FIAMMETTA
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Interleukin 2 ,Adult ,Antigens, Differentiation, T-Lymphocyte ,CD3 Complex ,CD3 ,T cell ,T-Lymphocytes ,Immunology ,CD2 Antigens ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,medicine ,Hypersensitivity ,Cytotoxic T cell ,Humans ,Receptors, Immunologic ,Interleukin 4 ,biology ,Lymphokine ,Receptors, Interleukin-2 ,T lymphocyte ,Molecular biology ,Recombinant Proteins ,stomatognathic diseases ,medicine.anatomical_structure ,biology.protein ,Interleukin-2 ,Interleukin-4 ,Cell activation ,medicine.drug ,Interleukin-1 ,Signal Transduction - Abstract
In the present work we analyzed the proliferative response of T lymphocytes from 11 atopic patients stimulated in vitro via either the CD2 or the CD3 pathway of cell activation. In both cases we found a significant decrease of thymidine incorporation in cell DNA in comparison with T cells from normal donors. The mechanism of this impaired proliferative response was analyzed. Atopic patients' T cells were found to secrete low quantities of interleukin 2 (IL2) and to express low amounts of Tac antigen, measured as both a percentage of Tac-positive cells and a mean fluorescence intensity of Tac antigen per cell. Addition of recombinant IL2 to cultures completely restored both cell proliferative response and Tac antigen expression. This effect was specific of IL2 since addition of IL1 or IL4 did not significantly affect T cell proliferative response. We conclude that atopic patients' T lymphocytes have a defect in both CD2 and CD3 pathways of cell activation relying on impairment of IL2 production, without involving IL2 responsiveness or other lymphokine defects.
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- 1992
7. Preliminary Investigation on the Ameliorative Role Exerted by D-Aspartic Acid in Counteracting Ethane Dimethane Sulfonate (EDS) Toxicity in the Rat Testis
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Massimo Venditti, Francesco Aniello, Maria Zelinda Romano, Sergio Minucci, Venditti, Massimo, Zelinda Romano, Maria, Aniello, Francesco, Minucci, Sergio, and Romano, Maria Zelinda
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0301 basic medicine ,medicine.medical_specialty ,PREP ,Antioxidant ,StAR ,medicine.medical_treatment ,Cell ,endocrine disrupters ,testis ,medicine.disease_cause ,Article ,EDS ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,D-aspartic acid ,lcsh:Zoology ,medicine ,TBARS ,Endocrine system ,lcsh:QL1-991 ,Testosterone ,lcsh:Veterinary medicine ,General Veterinary ,Chemistry ,testi ,Epithelium ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,030220 oncology & carcinogenesis ,Toxicity ,testosterone ,lcsh:SF600-1100 ,Animal Science and Zoology ,endocrine disrupter ,Oxidative stress - Abstract
Herein is reported the first evidence of the protective role of D-aspartic acid (D-Asp) in preventing the toxic effect exerted by the alkylating agent ethane dimethane sulfonate (EDS) in the rat testis. We confirmed that EDS treatment specifically destroyed Leydig cells (LC), resulting in the drastic decrease of the serum testosterone level and producing morphological changes in the germinal tubules, i.e., altered organization of the epithelium, loss of cell contacts and the consequent presence of empty spaces between them, and a reduce number of spermatozoa. Moreover, an increase of TUNEL-positive germ cells, other than alteration in the protein level and localization of two LC &ldquo, markers&rdquo, StAR and PREP, were observed. Interestingly, results obtained from rats pre-treated with D-Asp for 15 days before EDS-injection showed that all the considered parameters were quite normal. To explore the probable mechanism(s) involved in the protection exerted by D-Asp, we considered the increased oxidative stress induced by EDS and the D-Asp antioxidant effects. Thiobarbiturc acid-reactive species (TBARS) levels increased following EDS-injection, while no change was observed in the D-Asp + EDS treated rats. Our results showed that D-Asp may be used as a strategy to mitigate the toxic effects exerted by environmental pollutants, as endocrine disrupters, in order to preserve the reproductive function.
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- 2021
8. Alternative macrophage polarisation associated with resistance to anti-PD1 blockade is possibly supported by the splicing of FKBP51 immunophilin in melanoma patients
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Fortunato Ciardiello, Paolo D’ Arrigo, Emilio Francesco Giunta, Giuseppe Argenziano, Vincenza Vigorito, Martina Tufano, Teresa Troiani, Simona Romano, Maria Romano, Troiani, Teresa, Giunta, Emilio Francesco, Tufano, Martina, Vigorito, Vincenza, D'Arrigo, Paolo, Argenziano, Giuseppe, Ciardiello, Fortunato, Romano, MARIA FIAMMETTA, Romano, Simona, Troiani, T., Giunta, E. F., Tufano, M., Vigorito, V., Arrigo, P. D., Argenziano, G., Ciardiello, F., Romano, M. F., and Romano, S.
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Male ,Cancer Research ,Immune receptor ,Antibodies, Monoclonal, Humanized ,Peripheral blood mononuclear cell ,T-Lymphocytes, Regulatory ,Article ,B7-H1 Antigen ,Flow cytometry ,Tacrolimus Binding Proteins ,03 medical and health sciences ,Prognostic markers ,0302 clinical medicine ,Immunophenotyping ,Immune system ,medicine ,Gene silencing ,Humans ,Protein Isoforms ,Melanoma ,Immune Checkpoint Inhibitors ,030304 developmental biology ,Aged ,0303 health sciences ,medicine.diagnostic_test ,business.industry ,Monocyte ,Macrophages ,Macrophage Activation ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Nivolumab ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Immunotherapy ,business - Abstract
Background FKBP51 immunophilin is abundantly expressed by immune cells. Co-inhibitory immune receptor signalling generates the splicing isoform FKBP51s. Tregs stained by FKBP51s are increased in melanoma patients and their counts are associated with anti-CTLA-4 response. An expansion of FKBP51s+PD-L1+ monocytes was measured in a group of non-responding patients to anti-CTLA-4. The aim of this work was to confirm the predictive value of response of FKBP51s+Tregs in a cohort of patients undergoing anti-PD1 treatment and shed light on a monocyte subset co-expressing PD-L1/FKBP51s. Methods Co-cultures of organoids and autologous lymphocytes were used to confirm that tumour T-cell interaction can induce FKBP51s. PBMC immunophenotype and flow cytometry served to assess and monitor FKBP51s+Treg and FKBP51s+PD-L1+ monocytes in 22 advanced melanoma patients treated with anti-PD1. Silencing and overexpression of FKBP51s in human macrophages served to address the protein role in the tolerant macrophages’ behaviour. Results FKBP51s+Tregs count was increased in responders and had a prognostic value. Non-responders showed an early increase in FKBP51s+ PD-L1+ monocytes during anti-PD1 treatment. Manipulation of FKBP51s modulated the macrophage–phenotype, with forced protein expression promoting aspects associated with tolerance. Conclusions FKBP51s may guide in the selection and monitoring of melanoma patient candidates to immune-checkpoint-targeted therapy. Manipulation of FKBP51s may overcome resistance.
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- 2020
9. Evidence of melatonin ameliorative effects on the blood-testis barrier and sperm quality alterations induced by cadmium in the rat testis
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Sergio Minucci, Imed Messaoudi, Massimo Venditti, Russel J. Reiter, Maria Zelinda Romano, Mariem Ben Rhouma, Venditti, Massimo, Ben Rhouma, Mariem, Zelinda Romano, Maria, Messaoudi, Imed, Reiter, Russel J., and Minucci, Sergio
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Male ,endocrine system ,Health, Toxicology and Mutagenesis ,Motility ,Environmental pollution ,Melatonin ,Andrology ,Testis ,medicine ,Autophagy ,Animals ,GE1-350 ,Testosterone ,Blood-testis barrier ,Blood–testis barrier ,Chemistry ,Public Health, Environmental and Occupational Health ,Endocrine disrupters ,General Medicine ,Sertoli cell ,Pollution ,Sperm ,Spermatozoa ,Rats ,Environmental sciences ,medicine.anatomical_structure ,Melatonin, Endocrine disrupters, Cadmium, Testis, Blood-testis barrier, Autophagy ,TD172-193.5 ,Germ cell ,medicine.drug ,Cadmium - Abstract
Herein, we further document the protective action of melatonin (MLT) in mitigating cadmium (Cd)-induced toxicity on male adult rat testis. Cd treatment provoked testicular injury, that was documented by histological and biomolecular alterations, i.e., decrease of serum and testicular testosterone concentration and modified sperm parameters. Mainly, both the cytoarchitecture of the blood-testis barrier (BTB) and germ cell morphology were perturbed, as highlighted by impairment in structural (OCN, VANGL, Cx43) and regulative (Src and FAK) protein levels and/or activation. The study focused on the involvement of the autophagy pathway, that was enhanced especially in the Sertoli cells, probably in response to the disorganization of the BTB. Results obtained with the MLT co-treatment demonstrated that its administration decreased the level of oxidative damage caused by Cd, with reversal of all the observed changes. Moreover, the beneficial effects of MLT alone were evidenced by an increase of sperm quality, in term of motility and DNA integrity. The combined results, obtained in rat, strongly encourage to consider a role for MLT in improving also human testicular health, not only in men exposed to Cd, but also in those having fertility disorders, to ameliorate sperm quality and, consequently, reproductive success.
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- 2021
10. Optimization of an artificial neural network to study accelerations of foetal heart rhythm
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Giuseppe Cesarelli, Francesco Amato, Maria Romano, Alfonso Maria Ponsiglione, Ponsiglione, Alfonso Maria, Cesarelli, Giuseppe, Amato, Francesco, and Romano, Maria
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Coefficient of determination ,Artificial neural network ,medicine.diagnostic_test ,Mean squared error ,Foetal heart rhythm ,Computer science ,business.industry ,Predictive capability ,Pattern recognition ,Training methods ,fetal heart rate variability, artificial neural networks, machine learning, regression analysis ,Conjugate gradient method ,medicine ,Cardiotocography ,Artificial intelligence ,business - Abstract
Given the importance of accelerations of the foetal health rate (FHR) in the monitoring of the foetal wellbeing along the course of the pregnancy, and taking into consideration the contribution of computerized analysis of biosignals as well as the emerging role of artificial intelligence in medicine, this study describes the optimization and use of artificial neural networks (ANNs) as a tool for predicting and investigating FHR accelerations. To this aim, nineteen features have been extracted from 187 FHR signals recorded from healthy women by cardiotocography. Three training methods, including Levenberg-Marquardt (LM), Scaled Conjugate Gradient (SCG), and Bayesian Regularization (BR), have been tested by training ANNs with increasing number of neurons in the hidden layer. The optimal network configuration has been selected by checking at the coefficient of determination (R2) and the Root Mean Square Error (RMSE). Results suggest that a proper ANN configuration not only enables maximizing the predictive capability of the selected model but, mostly, could be helpful in investigating the influence of linear and nonlinear indices of the FHR variability (FHRV) on the total number of accelerations in the foetal heart rhythm.
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- 2021
11. Altered Expression of DAAM1 and PREP Induced by Cadmium Toxicity Is Counteracted by Melatonin in the Rat Testis
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Sergio Minucci, Mariem Ben Rhouma, Imed Messaoudi, Maria Zelinda Romano, Massimo Venditti, Russel J. Reiter, Venditti, Massimo, Ben Rhouma, Mariem, Zelinda Romano, Maria, Messaoudi, Imed, Reiter, Russel J., and Minucci, Sergio
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Male ,0301 basic medicine ,endocrine system ,PREP ,Somatic cell ,cadmium ,endocrine disrupters ,Apoptosis ,melatonin ,QH426-470 ,testis ,medicine.disease_cause ,Antioxidants ,Article ,Melatonin ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Genetics ,Animals ,Melatonin, Cadmium, Testis, Oxidative stress, Endocrine disrupters, Cytoskeleton, DAAM1, PREP ,oxidative stress ,Rats, Wistar ,Spermatogenesis ,Cytoskeleton ,Genetics (clinical) ,DAAM1 ,Chemistry ,cytoskeleton ,Rats ,Cytoskeletal Proteins ,030104 developmental biology ,Gene Expression Regulation ,Toxicity ,Prolyl Oligopeptidases ,030217 neurology & neurosurgery ,Oxidative stress ,medicine.drug - Abstract
Cadmium (Cd) is one of the most toxic pollutants for health due to its accumulation in several tissues, including testis. This report confirms that Cd increased oxidative stress and apoptosis of germ and somatic cells and provoked testicular injury, as documented by biomolecular and histological alterations, i.e., CAT and SOD activity, the protein level of steroidogenic enzymes (StAR and 3β-HSD), and morphometric parameters. Additionally, it further documents the melatonin (MLT) coadministration produces affects in mitigating Cd-induced toxicity on adult rat testis, as demonstrated by the reduction of oxidative stress and apoptosis, with reversal of the observed histological changes, moreover, a role of MLT in partially restoring steroidogenic enzymes expression was evidenced. Importantly, the cytoarchitecture of testicular cells was perturbed by Cd exposure, as highlighted by impairment of the expression and localization of two cytoskeleton-associated proteins DAAM1 and PREP, which are involved in the germ cells’ differentiation into spermatozoa, altering the normal spermatogenesis. Here, for the first time, we found that the co-treatment with MLT attenuated the Cd-induced toxicity on the testicular DAAM1 and PREP expression. The combined findings provide additional clues about a protective effect of MLT against Cd-induced testicular toxicity by acting on DAAM1 and PREP expression, encouraging further studies to prove its effectiveness in human health.
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- 2021
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12. Lean thinking to improve emergency department throughput at AORN Cardarelli hospital
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Anna Maria Ferraro, Maria Romano, Maria Vincenza Di Cicco, Ciro Verdoliva, Anna Borrelli, Mario Cesarelli, Maria Triassi, Giovanni Improta, Improta, Giovanni, Romano, Maria, Di Cicco, Maria Vincenza, Ferraro, Anna, Borrelli, Anna, Verdoliva, Ciro, Triassi, Maria, and Cesarelli, Mario
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Quality management ,Time Factors ,Time Factor ,Efficiency, Organizational ,Health informatics ,Lean manufacturing ,Health administration ,Workflow ,03 medical and health sciences ,0302 clinical medicine ,Hospital Administration ,Medicine ,Humans ,Operations management ,030212 general & internal medicine ,Quality improvement ,Lean thinking ,Organizational Case Studie ,Public health ,business.industry ,Emergency department ,030503 health policy & services ,Health Policy ,Nursing research ,lcsh:Public aspects of medicine ,lcsh:RA1-1270 ,Overcrowding ,Triage ,Italy ,Organizational Case Studies ,0305 other medical science ,business ,Emergency Service, Hospital ,Human ,Research Article - Abstract
Background Throughout the world, emergency departments (ED) are characterized by overcrowding and excessive waiting times. Furthermore, the related delays significantly increase patient mortality and make inefficient use of resources to the detriment of the satisfaction of employees and patients. In this work, lean thinking is applied to the ED of Cardarelli Hospital of Naples with the aim of increasing patient flow, improving the processes that contribute to facilitating the flow of patients through the various stages of medical treatment and eliminating all bottlenecks (queue) as well as all activities that generate waste. Methods This project was performed at National Hospital A.O.R.N. A. Cardarelli of Naples. The historical times of access to the ED were analysed from January 2015 to June 2015, for a total of 16,563 records. Subsequently, starting in November 2015, corrective actions were implemented according to the Lean Approach. Data collected after the introduced improvements were collected from April 2016 to June 2016 and compared to those collected during the starting period. Results The results acquired before application of the Lean Thinking strategy illustrated the as-is process with its drawbacks. An analysis of the non-added value activities was performed to identify the procedures that need to be improved. After implementation of the corrective actions, we observed a positive increase in the performance of the ED, quantified as percentages of hospitalized patients according to triage codes and waiting times. Conclusion This work demonstrates the applicability of Lean Thinking to ED processes and its effectiveness in terms of increasing the efficiency of services and reducing waste (waiting times).
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- 2018
13. Eradication of CSCs: the roadmap for curing cancer
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Maria Romano, Simona Romano, Martina Tufano, Elena Cesaro, Romano, Simona, Cesaro, Elena, Tufano, Martina, and Romano, MARIA FIAMMETTA
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Oncology ,PD-L1 ,Cancer Research ,medicine.medical_specialty ,cancer stem cell ,biology ,business.industry ,medicine.medical_treatment ,EMT ,targeted-therapy ,Targeted therapy ,TAM ,Cancer stem cell ,Internal medicine ,Research Perspective ,medicine ,biology.protein ,business ,Curing (chemistry) - Published
- 2020
14. Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene
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Mark M. Iles, Massimiliano Scalvenzi, Annalaura Montella, Zalman Vaksman, Mario Capasso, Daniela Formicola, Stefania Staibano, Alessandro Testori, Vito Alessandro Lasorsa, Hakon Hakonarson, Matteo Esposito, Sueva Cantalupo, Jan Koster, Paola Ghiorzo, Fabrizio Ayala, Sharon J. Diskin, Marcella Devoto, Antonella Cardinale, Marianna Avitabile, Flora Cimmino, Maria Fiammetta Romano, Maria Valeria Corrias, Mariangela Succoio, Nicola Zambrano, Virginia Andreotti, Matthew Law, Kevin M. Brown, Achille Iolascon, Avitabile, Marianna, Succoio, Mariangela, Testori, Alessandro, Cardinale, Antonella, Vaksman, Zalman, Lasorsa, Vito Alessandro, Cantalupo, Sueva, Esposito, Matteo, Cimmino, Flora, Montella, Annalaura, Formicola, Daniela, Koster, Jan, Andreotti, Virginia, Ghiorzo, Paola, Romano, Maria Fiammetta, Staibano, Stefania, Scalvenzi, Massimiliano, Ayala, Fabrizio, Hakonarson, Hakon, Corrias, Maria Valeria, Devoto, Marcella, Law, Matthew H, Iles, Mark M, Brown, Kevin, Diskin, Sharon, Zambrano, Nicola, Iolascon, Achille, Capasso, Mario, Oncogenomics, and CCA - Cancer biology and immunology
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0301 basic medicine ,Male ,Monocarboxylic Acid Transporters ,Cancer Research ,Neuroblastoma ,malignant cutaneous melanoma ,neural crest cells ,GWAS ,Skin Neoplasms ,Adrenal Gland Neoplasms ,Genome-wide association study ,Locus (genetics) ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Melanoma ,Cancer Biomarkers and Molecular Epidemiology ,Symporters ,Neural crest ,Cell Differentiation ,General Medicine ,Cell cycle ,medicine.disease ,030104 developmental biology ,Chromosomes, Human, Pair 1 ,Neural Crest ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Carcinogenesis ,Genome-Wide Association Study - Abstract
Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10−8). We also detected a suggestive (P < 10−7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10−4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1.
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- 2020
15. Opportunities and challenging issues of nanomaterials in otological fields: an occupational health perspective
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Veruscka Leso, Rosaria Romano, Maria Luigia Ercolano, Luca Fontana, Ivo Iavicoli, Leso, Veruscka, Fontana, L., Ercolano, MARIA LUIGIA, Romano, MARIA ROSARIA, and Iavicoli, Ivo
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Occupational risk ,Hearing loss ,otological application ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,02 engineering and technology ,Development ,Risk Assessment ,Occupational safety and health ,03 medical and health sciences ,Biosafety ,0302 clinical medicine ,medicine ,occupational risk ,Humans ,Nanotechnology ,General Materials Science ,030223 otorhinolaryngology ,Ear Diseases ,Occupational Health ,business.industry ,Perspective (graphical) ,cochlear implant ,biosafety ,imaging ,hearing lo ,Containment of Biohazards ,021001 nanoscience & nanotechnology ,Nanostructures ,ototoxicity ,Workforce ,drug delivery ,workers ,Engineering ethics ,nanomaterial ,medicine.symptom ,0210 nano-technology ,business - Abstract
Nanotechnology may offer innovative solutions to overcome the physiological and anatomical barriers that make the diagnosis and treatment of ear diseases an extremely challenging issue. However, despite the solutions provided by nano-applications, the still little-known toxicological behavior of nanomaterials raised scientific concerns regarding their biosafety for treated patients and exposed workers. Therefore, this review provides an overview on recent developments and upcoming opportunities in nanoscale otological applications, and critically assesses possible adverse effects of nanosized compounds on ear structures and hearing functionality. Although such preliminary data do not allow to draw definite strategies for the evaluation of nanomaterial ototoxicity, they can still be useful to improve scientific community and workforce awareness regarding possible nanomaterial adverse effects on ear.
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- 2019
16. Structural and dynamic studies provide insights into specificity and allosteric regulation of ribonuclease as, a key enzyme in mycobacterial virulence
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Maria Romano, Gabriella D'Auria, Luisa Calvanese, Rita Berisio, Lucia Falcigno, Flavia Squeglia, Calvanese, Luisa, Squeglia, Flavia, Romano, Maria, D'Auria, Gabriella, Falcigno, Lucia, and Berisio, Rita
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crystal structure ,RNase P ,Allosteric regulation ,Virulence ,RNA-binding protein ,medicine.disease_cause ,Substrate Specificity ,Mycobacterium tuberculosis ,Allosteric Regulation ,RNA, Transfer ,Structural Biology ,medicine ,Ribonuclease ,tRNA ,Molecular Biology ,Escherichia coli ,biology ,Chemistry ,Escherichia coli Proteins ,General Medicine ,biology.organism_classification ,tuberculosis ,Biochemistry ,Enzyme ,Transfer RNA ,biology.protein - Abstract
Ribonuclease AS (RNase AS) is a crucial enzyme for virulence of Mycobacterium tuberculosis. We previously observed that RNase AS structurally resembles RNase T from Escherichia coli, an important enzyme for tRNA maturation and turnover. Here, we combine X-ray crystallography and molecular dynamics (MD) to investigate the specificity and dynamic properties of substrate binding. Both X-ray and MD data provide structural determinants that corroborate the strict substrate specificity of RNase AS to cleave only adenosine residues, due to the structural features of adenine base. Beside suggesting tRNA as most likely substrate of RNase AS, MD and modeling studies identify key enzyme-ligand interactions, both involving the catalytic site and the double helix region of tRNA, which is locked by interactions with a set of arginine residues. The MD data also evidence a ligand-induced conformational change of the enzyme which is transferred from one chain to the adjacent one. These data will explain the dimeric nature of both RNase AS and RNase T, with two catalytic grooves composed of both chains. Also, they account for the dichotomy of tRNA, which contains both the substrate poly(A) chain and an inhibiting double strand RNA. Indeed, they provide a possible mechanism of allosteric regulation, which unlocks one catalytic groove when the second groove is inhibited by the double strand region of tRNA. Finally, a full comprehension of the molecular details of tRNA maturation processes is essential to develop novel strategies to modulate RNA processing, for therapeutic purposes. Abbreviations MD molecular dynamics PDB Protein Data Bank RMSD root mean square deviation RMSF root mean square fluctuation RNA ribonucleotidic acid RNase AS Ribonuclease AS Communicated by Ramasamy H. Sarma.
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- 2019
17. TRAF2 and FKBP51 as possible markers for identification of suitable melanoma tumors for tumor necrosis factor-α inhibition
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Stefania Staibano, Maria Fiammetta Romano, Martina Tufano, Gennaro Ilardi, Anna Rea, Paolo D'Arrigo, Francesco Merolla, Simona Romano, Antonello Petrella, Romano, Simona, D'Arrigo, Paolo, Tufano, Martina, Staibano, Stefania, Rea, Anna, Merolla, Francesco, Ilardi, Gennaro, Petrella, Antonello, and Romano, Maria F
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0301 basic medicine ,Cancer Research ,TRAF2 ,Skin Neoplasms ,medicine.medical_treatment ,nuclear factor-κB ,Dermatology ,IκB kinase ,Cell Line ,Tacrolimus Binding Proteins ,03 medical and health sciences ,0302 clinical medicine ,tumor necrosis factor receptor-Associated factor 2 ,Cell Line, Tumor ,medicine ,Humans ,Melanoma ,Tumor ,Chemistry ,FK506-binding protein 51 ,tumor necrosis factor-α ,Biomarkers ,TNF Receptor-Associated Factor 2 ,medicine.disease ,030104 developmental biology ,Cytokine ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,Tumor necrosis factor alpha - Abstract
Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine, whose role in melanoma is controversial. Although high-dose TNF-α is approved for the treatment of patients with in transit-metastatic melanoma confined to the limb, diverse preclinical models of melanoma have shown that TNF-α can induce cell invasion. Biomarkers that can differentiate between the dual role of TNF-α are needed. TRAF2 is critical to TNF receptor-induced activation of nuclear factor-κB (NF-κB), allowing shifting from death to survival-signaling cascades. The large immunophilin FKBP51 acts as a scaffold and catalyst in the IκB kinase complex assembly and activation. Here, using microscopy and an electrophoretic mobility-shift assay, we provide further evidence in support of the essential role of FKBP51 in sustaining the TNF-α NF-κB signaling in melanoma. Through the cross-linking reaction with the chemical linker disuccinimidyl glutarate, we show that a direct interaction occurs between FKBP51 and TRAF2 in melanoma cells. Immunohistochemistry of tumor samples from 24 patients with cutaneous melanomas showed a correlation between the expressions of the two proteins. Given the association of FKBP51 and TRAF2 with TNF-α-induced NF-κB signaling and their correlation in tumor samples, we propose that the two proteins can be exploited as useful markers for the identification of those melanoma tumors that can benefit from TNF-α inhibition. Future studies will address this hypothesis.
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- 2019
18. Oxidative Potential, Cytotoxicity, and Intracellular Oxidative Stress Generating Capacity of PM10: A Case Study in South of Italy
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Marianna Conte, Adelaide Dinoi, Daniele Contini, Maria Pia Romano, Maria Elena Giordano, Maria Rachele Guascito, Anna Rita De Bartolomeo, Roberto Caricato, Maria Giulia Lionetto, Lionetto, Maria Giulia, Guascito, Maria Rachele, Giordano, Maria Elena, Caricato, Roberto, DE BARTOLOMEO, Anna Rita, Romano, MARIA PIA, Conte, Marianna, Dinoi, Adelaide, and Contini, Daniele
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Atmospheric Science ,010504 meteorology & atmospheric sciences ,Oxidative phosphorylation ,lcsh:QC851-999 ,010501 environmental sciences ,Environmental Science (miscellaneous) ,intracellular oxidative stress generating capacity ,medicine.disease_cause ,complex mixtures ,01 natural sciences ,PM10 ,medicine ,Bioassay ,Food science ,Cytotoxicity ,0105 earth and related environmental sciences ,A549 cell ,oxidative potential ,Chemistry ,genotoxicity ,respiratory tract diseases ,Comet assay ,Toxicity ,cytotoxicity ,lcsh:Meteorology. Climatology ,Genotoxicity ,Oxidative stress - Abstract
Long and short-term exposure to atmospheric particulate matter (PM) has detrimental effects on human health. The effective mechanisms leading to PM toxicity are still not fully understood, even if it is known that physical-chemical properties, strongly influenced by sources and atmospheric processes, are known to play an important role. In this work, PM10 samples were collected, at an urban background site in southern Italy, to determine cytotoxicity (using MTT test on A549 cells), genotoxicity (using the comet assay), and intracellular oxidative stress on A549 cells exposed for 24 h to aqueous extracts of PM10 samples. Organic carbon (OC) and elemental carbon (EC) content of PM10 and acellular determination of oxidative potential with DTT assay were performed to compare results of acellular and cellular biological assays. Cellular (OSGCV and MTTV) and acellular (OPDTTV) outcomes, normalized in volume, are well correlated (statistically significant results) with carbon content suggesting that combustion sources play an important role in determining cellular oxidative stress and cytotoxicity of PM10. Even if the number of data is limited, genotoxicity results are well correlated (Pearson r >, 0.95) with OSGCV and MTTV, and a weaker, but statistically significant correlation was observed with OPDTTV. OSGCV is well correlated with the cell mortality observed with the MTTV test and a lower, but still statistically significant correlation is observed between MTTV and OPDDTV. A statistically significant correlation was found between OPDTTV and OSGCV results. When the outcomes of the cellular and acellular assay are compared normalized in mass (i.e., intrinsic values), the correlations become significantly weaker suggesting that the different sources acting on the site produces particulate matter with different toxicological potential influencing differently the biological tests studied.
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- 2021
19. Frequency and Time Domain Analysis of Foetal Heart Rate Variability with Traditional Indexes: A Critical Survey
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Maria Romano, Alfonso Maria Ponsiglione, Mario Cesarelli, Luigi Iuppariello, Giovanni Improta, Paolo Bifulco, Romano, Maria, Iuppariello, Luigi, Ponsiglione, alfonso maria, Improta, Giovanni, Bifulco, Paolo, and Cesarelli, Mario
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Male ,Cardiotocography ,Immunology and Microbiology (all) ,Gestational Age ,Review Article ,Foetal heart rate ,lcsh:Computer applications to medicine. Medical informatics ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Foetal growth ,Statistics ,medicine ,Humans ,Computer Simulation ,Time domain ,Fetal Monitoring ,Foetal heart rate variability ,Mathematics ,Biochemistry, Genetics and Molecular Biology (all) ,030219 obstetrics & reproductive medicine ,Fourier Analysis ,General Immunology and Microbiology ,medicine.diagnostic_test ,Medicine (all) ,Applied Mathematics ,Short Term Variability ,Infant, Newborn ,Reproducibility of Results ,Signal Processing, Computer-Assisted ,General Medicine ,Heart Rate, Fetal ,Models, Theoretical ,Applied Mathematic ,Modeling and Simulation ,Frequency domain ,embryonic structures ,lcsh:R858-859.7 ,Critical survey ,Female ,Algorithms ,030217 neurology & neurosurgery - Abstract
Monitoring of foetal heart rate and its variability (FHRV) covers an important role in assessing health of foetus. Many analysis methods have been used to get quantitative measures of FHRV. FHRV has been studied in time and in frequency domain and interesting clinical results have been obtained. Nevertheless, a standardized definition of FHRV and a precise methodology to be used for its evaluation are lacking. We carried out a literature overview about both frequency domain analysis (FDA) and time domain analysis (TDA). Then, by using simulated FHR signals, we defined the methodology for FDA. Further, employing more than 400 real FHR signals, we analysed some of the most common indexes, Short Term Variability for TDA and power content of the spectrum bands and sympathovagal balance for FDA, and evaluated their ranges of values, which in many cases are a novelty. Finally, we verified the relationship between these indexes and two important parameters: week of gestation, indicator of foetal growth, and foetal state, classified as active or at rest. Our results indicate that, according to literature, it is necessary to standardize the procedure for FHRV evaluation and to consider week of gestation and foetal state before FHR analysis.
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- 2016
20. Efficacy of the Regent Suit-based rehabilitation on gait EMG patterns in hemiparetic subjects: a pilot study
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Luigi Iuppariello, N. Pappone, Paolo Bifulco, Bernardo Lanzillo, Maria Romano, Mario Cesarelli, Giovanni D'Addio, Iuppariello, Luigi, D'Addio, Giovanni, Romano, Maria, Bifulco, Paolo, Pappone, Nicola, Lanzillo, Bernardo, and Cesarelli, Mario
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Adult ,Male ,030506 rehabilitation ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Pilot Projects ,Physical Therapy, Sports Therapy and Rehabilitation ,Electromyography ,law.invention ,Muscle coactivation ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,Randomized controlled trial ,law ,Activities of Daily Living ,medicine ,Humans ,Pilot Project ,Muscle, Skeletal ,education ,Gait Disorders, Neurologic ,education.field_of_study ,Rehabilitation ,Proprioception ,medicine.diagnostic_test ,business.industry ,Stroke Rehabilitation ,Robotics ,Middle Aged ,Gait ,Exercise Therapy ,Robotic ,Stroke ,Treatment Outcome ,medicine.anatomical_structure ,Berg Balance Scale ,Female ,0305 other medical science ,business ,030217 neurology & neurosurgery ,Human - Abstract
Background The recovery of the functional limb mobility of patients with cerebral damages can take great benefit of the role offered by proprioceptive rehabilitation. Recently have been developed a special Regent Suit (RS) for rehabilitative applications. Actually, there are preliminary studies which describes the effects of RS on gait recovery of stroke patients in acute stage, but none in chronic stage. Moreover, it is known that motor recovery does not always reflect improvements of the muscle activity and coactivity. Aim To investigate the effects of proprioceptive stimulation induced by the Regent Suit (RS) on the EMG patterns during gait in post-stroke chronic patients. Design Randomized controlled trial. Setting S. Maugeri Foundation, Telese Terme (BN), Italy. Population Patients have been randomly assigned into two equal groups of 20 patients: experimental group and traditional group. Further, a control group of 20 healthy subjects have been enrolled. Methods The traditional group attended a rehabilitation program composed by neuro-motor exercises without the RS, the experimental group performed the same rehabilitation program while wearing the RS. The NIH Stroke Scale (NIHSS), the Barthel Index (BI), the Functional Independent Measure (FIM) and the Berg Balance Scale (BBS) have been evaluated. EMG analysis has been performed considering the muscle activation timing over the gait of the soleus, tibialis anterior, semitendinosus and vastus lateralis muscles by decomposing the EMG signals into Gaussian pulses. Then, the symmetry of muscle activation and the muscle synergy patterns over the gait cycle have been assessed. Results The proprioceptive stimulation of the RS-based treatment induces higher and remarkable restoration of the normal muscle activation timing, also increasing the muscle symmetry and reducing the pathological muscle coactivation on both affected and non-affected sides. Conclusions These results suggest confirm that a RS-based treatment is more effective than usual care in improving the EMG patterns during locomotion and daily living activities in chronic post-stroke subjects. Clinical rehabilitation impact The proprioceptive rehabilitation Regent Suit based has an impact on motor function in stroke patients during gait.
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- 2018
21. Manipulation of the Immune System for Cancer Defeat: A Focus on the T Cell Inhibitory Checkpoint Molecules
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Maria Fiammetta Romano, Nunzia Novizio, Simona Romano, Vincenza Vigorito, Anna Rea, Martina Tufano, Salvatore Russo, Paolo D'Arrigo, D'Arrigo, Paolo, Tufano, Martina, Rea, Anna, Vigorito, Vincenza, Novizio, Nunzia, Russo, Salvatore, Romano, Maria Fiammetta, and Romano, Simona
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3-dioxygenase-1 ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,Programmed Cell Death 1 Receptor ,B7 homolog 4 protein (B7-H4) ,Biology ,Biochemistry ,Targeted therapy ,Immune tolerance ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neoplasms ,B7 homolog 3 protein (B7-H3) ,V-domain Ig suppressor of T cell activation (VISTA) ,Drug Discovery ,medicine ,Humans ,2 (IDO) ,Adenosine A2a receptor (A2aR) ,030304 developmental biology ,Pharmacology ,T cell immunoglobulin and mucin domain 3 (TIM-3) ,0303 health sciences ,Programmed cell Death 1 (PD-1) ,Immune-regulatory molecule indoleamine pyrrole-2 ,Organic Chemistry ,Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) ,Cancer ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Programmed Death-Ligand 1 (PD-L1) ,medicine.anatomical_structure ,Immunoediting ,B and T lymphocyte associated (BTLA) ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Lymphocyte Activation Gene-3 (LAG-3) ,Biomarkers - Abstract
The immune system actively counteracts the tumorigenesis process; a breakout of the immune system function, or its ability to recognize transformed cells, can favor cancer development. Cancer becomes able to escape from immune system control by using multiple mechanisms, which are only in part known at a cellular and molecular level. Among these mechanisms, in the last decade, the role played by the so-called “inhibitory immune checkpoints” is emerging as pivotal in preventing the tumor attack by the immune system. Physiologically, the inhibitory immune checkpoints work to maintain the self-tolerance and attenuate the tissue injury caused by pathogenic infections. Cancer cell exploits such immune-inhibitory molecules to contrast the immune intervention and induce tumor tolerance. Molecular agents that target these checkpoints represent the new frontier for cancer treatment. Despite the heterogeneity and multiplicity of molecular alterations among the tumors, the immune checkpoint targeted therapy has been shown to be helpful in selected and even histologically different types of cancer, and are currently being adopted against an increasing variety of tumors. The most frequently used is the moAb-based immunotherapy that targets the Programmed Cell Death 1 protein (PD-1), the PD-1 Ligand (PD-L1) or the cytotoxic T lymphocyte antigen-4 (CTLA4). However, new therapeutic approaches are currently in development, along with the discovery of new immune checkpoints exploited by the cancer cell. This article aims to review the inhibitory checkpoints, which are known up to now, along with the mechanisms of cancer immunoediting. An outline of the immune checkpoint targeting approaches, also including combined immunotherapies and the existing trials, is also provided. Notwithstanding the great efforts devoted by researchers in the field of biomarkers of response, to date, no validated FDA-approved immunological biomarkers exist for cancer patients. We highlight relevant studies on predictive biomarkers and attempt to discuss the challenges in this field, due to the complex and largely unknown dynamic mechanisms that drive the tumor immune tolerance.
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- 2018
22. Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death
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Lorenzo Memeo, Manaf Ali, Neetu Singh, Leroy Lowe, Lin Li, William H. Bisson, Jayadev Raju, Maria Romano, Dustin G. Brown, Rita Dornetshuber-Fleiss, Barry J. Barclay, Kannan Badri Narayanan, Simona Romano, Yon Rojanasakul, Tae-Jin Lee, A. Ivana Scovassi, Annamaria Colacci, Edward A. Ratovitski, Leandro S. D'Abronzo, Rabindra Roy, Michael J. Gonzalez Guzman, Hyun Ho Park, Jordan Woodrick, Fahd Al-Mulla, Amedeo Amedei, Clement G. Yedjou, Monica Vaccari, Qiang Shawn Cheng, Paramita M. Ghosh, Rabeah Al-Temaimi, Seo Yun Kim, Roslida Abd Hamid, Chiara Mondello, Elizabeth P. Ryan, Stefano Forte, Ranjeet Kumar Sinha, Hosni Salem, Po Sing Leung, Suidjit Luanpitpong, Narayanan, Kannan Badri, Ali, Manaf, Barclay, Barry J, Cheng, Qiang Shawn, D'Abronzo, Leandro, Dornetshuber Fleiss, Rita, Ghosh, Paramita M, Gonzalez Guzman, Michael J, Lee, Tae Jin, Leung, Po Sing, Li, Lin, Luanpitpong, Suidjit, Ratovitski, Edward, Rojanasakul, Yon, Romano, MARIA FIAMMETTA, Romano, Simona, Sinha, Ranjeet K, Yedjou, Clement, Al Mulla, Fahd, Al Temaimi, Rabeah, Amedei, Amedeo, Brown, Dustin G, Ryan, Elizabeth P, Colacci, Annamaria, Hamid, Roslida A, Mondello, Chiara, Raju, Jayadev, Salem, Hosni K, Woodrick, Jordan, Scovassi, A. Ivana, Singh, Neetu, Vaccari, Monica, Roy, Rabindra, Forte, Stefano, Memeo, Lorenzo, Kim, Seo Yun, Bisson, William H, Lowe, Leroy, and Park, Hyun Ho
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Cancer Research ,Programmed cell death ,Carcinogenesis ,Oncology and Carcinogenesis ,Review ,Biology ,medicine.disease_cause ,Hazardous Substances ,Environmental ,Neoplasms ,Homeostasi ,medicine ,Animals ,Humans ,Homeostasis ,2.1 Biological and endogenous factors ,Oncology & Carcinogenesis ,Carcinogenesi ,Organism ,Carcinogen ,Tissue homeostasis ,Cancer ,Cell Death ,Animal ,Environmental Exposure ,General Medicine ,Carcinogens, Environmental ,Cell biology ,Apoptosis ,Hazardous Substance ,Immunology ,Environmental Carcinogenesis ,Carcinogens ,Generic health relevance ,Signal transduction ,Human - Abstract
Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis.
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- 2015
23. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead
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Dustin G. Brown, Tove Hultman, Judith Weisz, H. Kim Lyerly, Paola A. Marignani, Ann-Karin Olsen, Rabindra Roy, Kim Moorwood, Masoud H. Manjili, Monica Vaccari, Jesse Roman, Hasiah Ab Hamid, Kalan R. Prudhomme, Periyadan K. Krishnakumar, Chenfang Dong, Tiziana Guarnieri, Leandro S. D'Abronzo, Gloria M. Calaf, Amelia K Charles, Emanuela Corsini, Yunus A. Luqmani, Graeme Williams, Louis Vermeulen, Pankaj Vadgama, Sarah N Bay, Véronique Maguer-Satta, Sabine A. S. Langie, Christian C. Naus, Le Jian, Gladys N. Nangami, Lorenzo Memeo, Stephanie C. Casey, Thomas Sanderson, Takemi Otsuki, Nichola Cruickshanks, William H. Bisson, Sudjit Luanpitpong, Jonathan Whitfield, Ahmed Lasfar, Yon Rojanasakul, A. Ivana Scovassi, Shelley A. Harris, Ferdinando Chiaradonna, Richard Ponce-Cusi, Gregory T. Wolf, Valérian Dormoy, Roslida Abd Hamid, Hyun Ho Park, Matilde E. Lleonart, William K. Decker, Maria Romano, Leroy Lowe, Fabio Marongiu, Jan Vondráček, Chiara Mondello, Luc Leyns, Josiah Ochieng, Pratima Nangia-Makker, Edward A. Ratovitski, Zhiwei Hu, Jayadev Raju, Hemad Yasaei, Rafaela Andrade-Vieira, Jordan Woodrick, Hideko Sone, Harini Krishnan, W. Kimryn Rathmell, Andrew Collins, Luoping Zhang, Barry J. Barclay, Amaya Azqueta, Laura Soucek, Marc A. Williams, David O. Carpenter, Roberta Palorini, Rita Nahta, Juan Fernando Martinez-Leal, Firouz Darroudi, Rita Dornetshuber-Fleiss, James E. Klaunig, Elizabeth P. Ryan, Qiang Shawn Cheng, Arthur Berg, Andrew Ward, Gudrun Koppen, Tao Chen, Petr Heneberg, Michael Gilbertson, Amedeo Amedei, Sakina E. Eltom, Ezio Laconi, Joseph Christopher, Hiroshi Kondoh, Neetu Singh, Danielle J Carlin, Marion Chapellier, Michalis V. Karamouzis, Rekha Mehta, Tae-Jin Lee, Annamaria Colacci, Venkata S. Sabbisetti, Mark Wade, Micheline Kirsch-Volders, Patricia Ostrosky-Wegman, Isabelle R. Miousse, Patricia A. Thompson, Philippa D. Darbre, Frederik J. van Schooten, Sofia Pavanello, Igor Koturbash, Binhua P. Zhou, Ranjeet Kumar Sinha, Anna C. Salzberg, Mahara Valverde, Fahd Al-Mulla, Julia Kravchenko, Nicole Kleinstreuer, Carolyn J. Baglole, Menghang Xia, Samira A. Brooks, Amancio Carnero, Gunnar Brunborg, Sandra S. Wise, Daniel C. Koch, John Pierce Wise, Rabeah Al-Temaimi, Laetitia Gonzalez, Lisa J. McCawley, R. Brooks Robey, Gary S. Goldberg, Thierry Massfelder, Linda S M Gulliver, Olugbemiga Ogunkua, Emilio Rojas, Eun-Yi Moon, Lin Li, Silvana Papagerakis, Nik van Larebeke, Adela Lopez de Cerain Salsamendi, Staffan Eriksson, Simona Romano, Dean W. Felsher, Paramita M. Ghosh, Karine A. Cohen-Solal, Paul Dent, Jun Sun, Carmen Blanco-Aparicio, Riccardo Di Fiore, Chia-Wen Hsu, Mahin Khatami, Kannan Badri Narayanan, Francis Martin, Colleen S. Curran, Dale W. Laird, William H. Goodson, Abdul Manaf Ali, Valerie Odero-Marah, Michael J. Gonzalez, Renza Vento, Liang Tzung Lin, Clement G. Yedjou, Hosni Salem, Hsue-Yin Hsu, Zhenbang Chen, Nuzhat Ahmed, Gerard Wagemaker, Sandra Ryeom, Stefano Forte, Debasish Roy, Nancy B. Kuemmerle, Robert C. Castellino, Po Sing Leung, Wilhelm Engström, National Institute of Environmental Health Sciences (US), Research Council of Norway, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa en Cáncer (España), European Commission, Junta de Andalucía, Ministerio de Educación y Ciencia (España), Ministero dell'Istruzione, dell'Università e della Ricerca, University of Oslo, Regione Emilia Romagna, National Institutes of Health (US), Consejo Nacional de Ciencia y Tecnología (México), Associazione Italiana per la Ricerca sul Cancro, National Research Foundation of Korea, Ministry of Education, Science and Technology (South Korea), Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), Ministry of Education, Culture, Sports, Science and Technology (Japan), Japan Science and Technology Agency, Ministry of Science and Technology (Taiwan), Arkansas Biosciences Institute, Czech Science Foundation, Fundación Fero, Swim Across America, American Cancer Society, Research Foundation - Flanders, Austrian Science Fund, Institut National de la Santé et de la Recherche Médicale (France), Natural Sciences and Engineering Research Council of Canada, Farmacologie en Toxicologie, RS: NUTRIM - R4 - Gene-environment interaction, Goodson, William H, Lowe, Leroy, Carpenter, David O, Gilbertson, Michael, Manaf Ali, Abdul, Lopez de Cerain Salsamendi, Adela, Lasfar, Ahmed, Carnero, Amancio, Azqueta, Amaya, Amedei, Amedeo, Charles, Amelia K, Collins, Andrew R, Ward, Andrew, Salzberg, Anna C, Colacci, Annamaria, Olsen, Ann Karin, Berg, Arthur, Barclay, Barry J, Zhou, Binhua P, Blanco Aparicio, Carmen, Baglole, Carolyn J, Dong, Chenfang, Mondello, Chiara, Hsu, Chia Wen, Naus, Christian C, Yedjou, Clement, Curran, Colleen S, Laird, Dale W, Koch, Daniel C, Carlin, Danielle J, Felsher, Dean W, Roy, Debasish, Brown, Dustin G, Ratovitski, Edward, Ryan, Elizabeth P, Corsini, Emanuela, Rojas, Emilio, Moon, Eun Yi, Laconi, Ezio, Marongiu, Fabio, Al Mulla, Fahd, Chiaradonna, Ferdinando, Darroudi, Firouz, Martin, Francis L, Van Schooten, Frederik J, Goldberg, Gary S, Wagemaker, Gerard, Nangami, Gladys N, Calaf, Gloria M, Williams, Graeme, Wolf, Gregory T, Koppen, Gudrun, Brunborg, Gunnar, Lyerly, H. Kim, Krishnan, Harini, Ab Hamid, Hasiah, Yasaei, Hemad, Sone, Hideko, Kondoh, Hiroshi, Salem, Hosni K, Hsu, Hsue Yin, Park, Hyun Ho, Koturbash, Igor, Miousse, Isabelle R, Scovassi, A. Ivana, Klaunig, James E, Vondráček, Jan, Raju, Jayadev, Roman, Jesse, Wise, John Pierce, Whitfield, Jonathan R, Woodrick, Jordan, Christopher, Joseph A, Ochieng, Josiah, Martinez Leal, Juan Fernando, Weisz, Judith, Kravchenko, Julia, Sun, Jun, Prudhomme, Kalan R, Narayanan, Kannan Badri, Cohen Solal, Karine A, Moorwood, Kim, Gonzalez, Laetitia, Soucek, Laura, Jian, Le, D'Abronzo, Leandro S, Lin, Liang Tzung, Li, Lin, Gulliver, Linda, Mccawley, Lisa J, Memeo, Lorenzo, Vermeulen, Loui, Leyns, Luc, Zhang, Luoping, Valverde, Mahara, Khatami, Mahin, Romano, MARIA FIAMMETTA, Chapellier, Marion, Williams, Marc A, Wade, Mark, Manjili, Masoud H, Lleonart, Matilde E, Xia, Menghang, Gonzalez, Michael J, Karamouzis, Michalis V, Kirsch Volders, Micheline, Vaccari, Monica, Kuemmerle, Nancy B, Singh, Neetu, Cruickshanks, Nichola, Kleinstreuer, Nicole, van Larebeke, Nik, Ahmed, Nuzhat, Ogunkua, Olugbemiga, Krishnakumar, P. K, Vadgama, Pankaj, Marignani, Paola A, Ghosh, Paramita M, Ostrosky Wegman, Patricia, Thompson, Patricia A, Dent, Paul, Heneberg, Petr, Darbre, Philippa, Sing Leung, Po, Nangia Makker, Pratima, Cheng, Qiang Shawn, Robey, R. Brook, Al Temaimi, Rabeah, Roy, Rabindra, Andrade Vieira, Rafaela, Sinha, Ranjeet K, Mehta, Rekha, Vento, Renza, Di Fiore, Riccardo, Ponce Cusi, Richard, Dornetshuber Fleiss, Rita, Nahta, Rita, Castellino, Robert C, Palorini, Roberta, Abd Hamid, Roslida, Langie, Sabine A. S, Eltom, Sakina E, Brooks, Samira A, Ryeom, Sandra, Wise, Sandra S, Bay, Sarah N, Harris, Shelley A, Papagerakis, Silvana, Romano, Simona, Pavanello, Sofia, Eriksson, Staffan, Forte, Stefano, Casey, Stephanie C, Luanpitpong, Sudjit, Lee, Tae Jin, Otsuki, Takemi, Chen, Tao, Massfelder, Thierry, Sanderson, Thoma, Guarnieri, Tiziana, Hultman, Tove, Dormoy, Valérian, Odero Marah, Valerie, Sabbisetti, Venkata, Maguer Satta, Veronique, Rathmell, W. Kimryn, Engström, Wilhelm, Decker, William K, Bisson, William H, Rojanasakul, Yon, Luqmani, Yunu, Chen, Zhenbang, Hu, Zhiwei, Goodson, W., Lowe, L., Carpenter, D., Gilbertson, M., Ali, A., de Cerain Salsamendi, A., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., Charles, A., Collins, A., Ward, A., Salzberg, A., Colacci, A., Olsen, A., Berg, A., Barclay, B., Zhou, B., Blanco-Aparicio, C., Baglole, C., Dong, C., Mondello, C., Hsu, C., Naus, C., Yedjou, C., Curran, C., Laird, D., Koch, D., Carlin, D., Felsher, D., Roy, D., Brown, D., Ratovitski, E., Ryan, E., Corsini, E., Rojas, E., Moon, E., Laconi, E., Marongiu, F., Al-Mulla, F., Chiaradonna, F., Darroudi, F., Martin, F., Van Schooten, F., Goldberg, G., Wagemaker, G., Nangami, G., Calaf, G., Williams, G., Wolf, G., Koppen, G., Brunborg, G., Kim Lyerly, H., Krishnan, H., Hamid, H., Yasaei, H., Sone, H., Kondoh, H., Salem, H., Hsu, H., Park, H., Koturbash, I., Miousse, I., Ivana Scovassi, A., Klaunig, J., Vondráček, J., Raju, J., Roman, J., Wise, J., Whitfield, J., Woodrick, J., Christopher, J., Ochieng, J., Martinez-Leal, J., Weisz, J., Kravchenko, J., Sun, J., Prudhomme, K., Narayanan, K., Cohen-Solal, K., Moorwood, K., Gonzalez, L., Soucek, L., Jian, L., D'Abronzo, L., Lin, L., Li, L., Gulliver, L., Mccawley, L., Memeo, L., Vermeulen, L., Leyns, L., Zhang, L., Valverde, M., Khatami, M., Romano, M., Chapellier, M., Williams, M., Wade, M., Manjili, M., Lleonart, M., Xia, M., Gonzalez, M., Karamouzis, M., Kirsch-Volders, M., Vaccari, M., Kuemmerle, N., Singh, N., Cruickshanks, N., Kleinstreuer, N., Van Larebeke, N., Ahmed, N., Ogunkua, O., Krishnakumar, P., Vadgama, P., Marignani, P., Ghosh, P., Ostrosky-Wegman, P., Thompson, P., Dent, P., Heneberg, P., Darbre, P., Leung, P., Nangia-Makker, P., Cheng, Q., Brooks Robey, R., Al-Temaimi, R., Roy, R., Andrade-Vieira, R., Sinha, R., Mehta, R., Vento, R., Di Fiore, R., Ponce-Cusi, R., Dornetshuber-Fleiss, R., Nahta, R., Castellino, R., Palorini, R., Hamid, R., Langie, S., Eltom, S., Brooks, S., Ryeom, S., Wise, S., Bay, S., Harris, S., Papagerakis, S., Romano, S., Pavanello, S., Eriksson, S., Forte, S., Casey, S., Luanpitpong, S., Lee, T., Otsuki, T., Chen, T., Massfelder, T., Sanderson, T., Guarnieri, T., Hultman, T., Dormoy, V., Odero-Marah, V., Sabbisetti, V., Maguer-Satta, V., Kimryn Rathmell, W., Engström, W., Decker, W., Bisson, W., Rojanasakul, Y., Luqmani, Y., Chen, Z., Hu, Z., Goodson, W.H., Carpenter, D.O., Ali, A.M., de Cerain Salsamendi, A.L., Charles, A.K., Collins, A.R., Salzberg, A.C., Olsen, A.-K., Barclay, B.J., Zhou, B.P., Baglole, C.J., Hsu, C.-W., Naus, C.C., Curran, C.S., Laird, D.W., Koch, D.C., Carlin, D.J., Felsher, D.W., Brown, D.G., Ryan, E.P., Moon, E.-Y., Martin, F.L., Van Schooten, F.J., Goldberg, G.S., Calaf, G.M., Wolf, G.T., Hamid, H.A., Salem, H.K., Hsu, H.-Y., Park, H.H., Miousse, I.R., Klaunig, J.E., Vondracek, J., Wise, J.P., Whitfield, J.R., Christopher, J.A., Martinez-Leal, J.F., Prudhomme, K.R., Narayanan, K.B., Cohen-Solal, K.A., D'Abronzo, L.S., Lin, L.-T., Mccawley, L.J., Romano, M.F., Williams, M.A., Manjili, M.H., Gonzalez, M.J., Karamouzis, M.V., Kuemmerle, N.B., Krishnakumar, P.K., Marignani, P.A., Ghosh, P.M., Leung, P.S., Cheng, Q.S., Sinha, R.K., Castellino, R.C., Hamid, R.A., Langie, S.A.S., Brooks, S.A., Wise, S.S., Bay, S.N., Harris, S.A., Casey, S.C., Lee, T.-J., Engstrom, W., Decker, W.K., Bisson, W.H., sans affiliation, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276), Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript, William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation, Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia, Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey, Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012), Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support, Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012), Andrew R.Collins was supported by the University of Oslo, Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy, Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S), Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370), Christian C.Naus holds a Canada Research Chair, Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581), Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151, Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964), Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS), Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea, Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06), Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro, IG 15364), Francis L.Martin acknowledges funding from Rosemere Cancer Foundation, he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years, Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation, Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA), Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium, Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697), Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST, Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002), Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449), Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S), Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health, Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain, Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology, Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback, Jun Sun is supported by a Swim Across America Cancer Research Award, Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE), Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07), Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain, Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19), Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand, Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164), Mahara Valverde would like to thank CONACyT support 153781, Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India, Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C), P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association, Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774), Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y, Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021, Qiang Cheng was supported in part by grant NSF IIS-1218712, R. Brooks Robey is supported by the United States Department of Veterans Affairs, Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447), Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007, Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013), Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung, Roberta Palorini is supported by a SysBioNet fellowship, Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165, Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013, Sakina Eltom is supported by NIH grant SC1CA153326, Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship, Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation, Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg, Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR, MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC, 313313) and the California Breast Cancer Research Program (CBCRP, 17UB-8703), Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy, W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society, William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas, William H.Bisson was supported with funding from the NIH P30 ES000210, Yon Rojanasakul was supported with NIH grant R01-ES022968, Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593), Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program., Sans affiliation, Courcelles, Michel, Goodson, W, Lowe, L, Carpenter, D, Gilbertson, M, Ali, A, de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, A, Collins, A, Ward, A, Salzberg, A, Colacci, A, Olsen, A, Berg, A, Barclay, B, Zhou, B, Blanco Aparicio, C, Baglole, C, Dong, C, Mondello, C, Hsu, C, Naus, C, Yedjou, C, Curran, C, Laird, D, Koch, D, Carlin, D, Felsher, D, Roy, D, Brown, D, Ratovitski, E, Ryan, E, Corsini, E, Rojas, E, Moon, E, Laconi, E, Marongiu, F, Al Mulla, F, Chiaradonna, F, Darroudi, F, Martin, F, Van Schooten, F, Goldberg, G, Wagemaker, G, Nangami, G, Calaf, G, Williams, G, Wolf, G, Koppen, G, Brunborg, G, Kim Lyerly, H, Krishnan, H, Hamid, H, Yasaei, H, Sone, H, Kondoh, H, Salem, H, Hsu, H, Park, H, Koturbash, I, Miousse, I, Ivana Scovassi, A, Klaunig, J, Vondráček, J, Raju, J, Roman, J, Wise, J, Whitfield, J, Woodrick, J, Christopher, J, Ochieng, J, Martinez Leal, J, Weisz, J, Kravchenko, J, Sun, J, Prudhomme, K, Narayanan, K, Cohen Solal, K, Moorwood, K, Gonzalez, L, Soucek, L, Jian, L, D'Abronzo, L, Lin, L, Li, L, Gulliver, L, Mccawley, L, Memeo, L, Vermeulen, L, Leyns, L, Zhang, L, Valverde, M, Khatami, M, Romano, M, Chapellier, M, Williams, M, Wade, M, Manjili, M, Lleonart, M, Xia, M, Gonzalez, M, Karamouzis, M, Kirsch Volders, M, Vaccari, M, Kuemmerle, N, Singh, N, Cruickshanks, N, Kleinstreuer, N, Van Larebeke, N, Ahmed, N, Ogunkua, O, Krishnakumar, P, Vadgama, P, Marignani, P, Ghosh, P, Ostrosky Wegman, P, Thompson, P, Dent, P, Heneberg, P, Darbre, P, Leung, P, Nangia Makker, P, Cheng, Q, Brooks Robey, R, Al Temaimi, R, Roy, R, Andrade Vieira, R, Sinha, R, Mehta, R, Vento, R, Di Fiore, R, Ponce Cusi, R, Dornetshuber Fleiss, R, Nahta, R, Castellino, R, Palorini, R, Hamid, R, Langie, S, Eltom, S, Brooks, S, Ryeom, S, Wise, S, Bay, S, Harris, S, Papagerakis, S, Romano, S, Pavanello, S, Eriksson, S, Forte, S, Casey, S, Luanpitpong, S, Lee, T, Otsuki, T, Chen, T, Massfelder, T, Sanderson, T, Guarnieri, T, Hultman, T, Dormoy, V, Odero Marah, V, Sabbisetti, V, Maguer Satta, V, Kimryn Rathmell, W, Engström, W, Decker, W, Bisson, W, Rojanasakul, Y, Luqmani, Y, Chen, Z, and Hu, Z
- Subjects
Cancer Research ,Carcinogenesis ,[SDV]Life Sciences [q-bio] ,METHOXYCHLOR-INDUCED ALTERATIONS ,Review ,Pharmacology ,MESH: Carcinogens, Environmental ,Carcinogenic synergies ,Chemical mixtures ,Neoplasms ,MESH: Animals ,MESH: Neoplasms ,Carcinogenesi ,Risk assessment ,Cancer ,ACTIVATED PROTEIN-KINASES ,Medicine (all) ,Low dose ,1. No poverty ,Cumulative effects ,BREAST-CANCER CELLS ,General Medicine ,Environmental exposure ,MESH: Carcinogenesis ,BIO/10 - BIOCHIMICA ,EPITHELIAL-MESENCHYMAL TRANSITION ,3. Good health ,[SDV] Life Sciences [q-bio] ,Environmental Carcinogenesis ,ESTROGEN-RECEPTOR-ALPHA ,Human ,MESH: Environmental Exposure ,ENDOCRINE-DISRUPTING CHEMICALS ,TARGETING TISSUE FACTOR ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Prototypical chemical disruptors ,Exposure ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Environmental health ,medicine ,[SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health ,Carcinogen ,Environmental carcinogenesis ,[SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health ,MESH: Humans ,Animal ,POLYBROMINATED DIPHENYL ETHERS ,Environmental Exposure ,medicine.disease ,MESH: Hazardous Substances ,Carcinogens, Environmental ,MIGRATION INHIBITORY FACTOR ,VASCULAR ENDOTHELIAL-CELLS ,Hazardous Substance ,Neoplasm - Abstract
Goodson, William H. et al., © The Author 2015. Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology., We gratefully acknowledge the support of the National Institute of Health-National Institute of Environmental Health Sciences (NIEHS) conference grant travel support (R13ES023276); Glenn Rice, Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA also deserves thanks for his thoughtful feedback and inputs on the manuscript; William H.Goodson III was supported by the California Breast Cancer Research Program, Clarence Heller Foundation and California Pacific Medical Center Foundation; Abdul M.Ali would like to acknowledge the financial support of the University of Sultan Zainal Abidin, Malaysia; Ahmed Lasfar was supported by an award from the Rutgers Cancer Institute of New Jersey; Ann-Karin Olsen and Gunnar Brunborg were supported by the Research Council of Norway (RCN) through its Centres of Excellence funding scheme (223268/F50), Amancio Carnero’s lab was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012); Matilde E. Lleonart was supported by a trienal project grant PI12/01104 and by project CP03/00101 for personal support. Amaya Azqueta would like to thank the Ministerio de Educacion y Ciencia (‘Juande la Cierva’ programme, 2009) of the Spanish Government for personal support; Amedeo Amedei was supported by the Italian Ministry of University and Research (2009FZZ4XM_002), and the University of Florence (ex60%2012); Andrew R.Collins was supported by the University of Oslo; Annamaria Colacci was supported by the Emilia-Romagna Region - Project ‘Supersite’ in Italy; Carolyn Baglole was supported by a salary award from the Fonds de recherche du Quebec-Sante (FRQ-S); Chiara Mondello’s laboratory is supported by Fondazione Cariplo in Milan, Italy (grant n. 2011-0370); Christian C.Naus holds a Canada Research Chair; Clement Yedjou was supported by a grant from the National Institutes of Health (NIH-NIMHD grant no. G12MD007581); Daniel C.Koch is supported by the Burroughs Wellcome Fund Postdoctoral Enrichment Award and the Tumor Biology Training grant: NIH T32CA09151; Dean W. Felsher would like to acknowledge the support of United States Department of Health and Human Services, NIH grants (R01 CA170378 PQ22, R01 CA184384, U54 CA149145, U54 CA151459, P50 CA114747 and R21 CA169964); Emilio Rojas would like to thank CONACyT support 152473, Ezio Laconi was supported by AIRC (Italian Association for Cancer Research, grant no. IG 14640) and by the Sardinian Regional Government (RAS); Eun-Yi Moon was supported by grants from the Public Problem-Solving Program (NRF-015M3C8A6A06014500) and Nuclear R&D Program (#2013M2B2A9A03051296 and 2010-0018545) through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education, Science and Technology (MEST) in Korea; Fahd Al-Mulla was supported by the Kuwait Foundation for the Advancement of Sciences (2011-1302-06); Ferdinando Chiaradonna is supported by SysBioNet, a grant for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI) and by AIRC (Associazione Italiana Ricerca sul Cancro; IG 15364); Francis L.Martin acknowledges funding from Rosemere Cancer Foundation; he also thanks Lancashire Teaching Hospitals NHS trust and the patients who have facilitated the studies he has undertaken over the course of the last 10 years; Gary S.Goldberg would like to acknowledge the support of the New Jersey Health Foundation; Gloria M.Calaf was supported by Fondo Nacional de Ciencia y Tecnología (FONDECYT), Ministerio de Educación de Chile (MINEDUC), Universidad de Tarapacá (UTA); Gudrun Koppen was supported by the Flemish Institute for Technological Research (VITO), Belgium; Hemad Yasaei was supported from a triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction (NC3Rs) of animals in research (NC.K500045.1 and G0800697); Hiroshi Kondoh was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Science and Technology Agency and by JST, CREST; Hsue-Yin Hsu was supported by the Ministry of Science and Technology of Taiwan (NSC93-2314-B-320-006 and NSC94-2314-B-320-002); Hyun Ho Park was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) of the Ministry of Education, Science and Technology (2012R1A2A2A01010870) and a grant from the Korea Healthcare Technology R&D project, Ministry of Health and Welfare, Republic of Korea (HI13C1449); Igor Koturbash is supported by the UAMS/NIH Clinical and Translational Science Award (UL1TR000039 and KL2TR000063) and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000; Jan Vondráček acknowledges funding from the Czech Science Foundation (13-07711S); Jesse Roman thanks the NIH for their support (CA116812), John Pierce Wise Sr. and Sandra S.Wise were supported by National Institute of Environmental Health Sciences (ES016893 to J.P.W.) and the Maine Center for Toxicology and Environmental Health; Jonathan Whitfield acknowledges support from the FERO Foundation in Barcelona, Spain; Joseph Christopher is funded by Cancer Research UK and the International Journal of Experimental Pathology; Julia Kravchenko is supported by a philanthropic donation by Fred and Alice Stanback; Jun Sun is supported by a Swim Across America Cancer Research Award; Karine A.Cohen-Solal is supported by a research scholar grant from the American Cancer Society (116683-RSG-09-087-01-TBE); Laetitia Gonzalez received a postdoctoral fellowship from the Fund for Scientific Research–Flanders (FWO-Vlaanderen) and support by an InterUniversity Attraction Pole grant (IAP-P7-07); Laura Soucek is supported by grant #CP10/00656 from the Miguel Servet Research Contract Program and acknowledges support from the FERO Foundation in Barcelona, Spain; Liang-Tzung Lin was supported by funding from the Taipei Medical University (TMU101-AE3-Y19); Linda Gulliver is supported by a Genesis Oncology Trust (NZ) Professional Development Grant, and the Faculty of Medicine, University of Otago, Dunedin, New Zealand; Louis Vermeulen is supported by a Fellowship of the Dutch Cancer Society (KWF, UVA2011-4969) and a grant from the AICR (14–1164); Mahara Valverde would like to thank CONACyT support 153781; Masoud H. Manjili was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087 Neetu Singh was supported by grant #SR/FT/LS-063/2008 from the Department of Science and Technology, Government of India; Nicole Kleinstreuer is supported by NIEHS contracts (N01-ES 35504 and HHSN27320140003C); P.K. Krishnakumar is supported by the Funding (No. T.K. 11-0629) of King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia; Paola A.Marignani is supported by the Dalhousie Medical Research Foundation, The Beatrice Hunter Cancer Institute and CIHR and the Nova Scotia Lung Association; Paul Dent is the holder of the Universal Inc.Chair in Signal Transduction Research and is supported with funds from PHS grants from the NIH (R01-CA141704, R01-CA150214, R01-DK52825 and R01-CA61774); Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, and by the Czech Science Foundation projects P301/12/1686 and 15-03834Y; Po Sing Leung was supported by the Health and Medical Research Fund of Food and Health Bureau, Hong Kong Special Administrative Region, Ref. No: 10110021; Qiang Cheng was supported in part by grant NSF IIS-1218712; R. Brooks Robey is supported by the United States Department of Veterans Affairs; Rabindra Roy was supported by United States Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1 and RO1 CA113447); Rafaela Andrade-Vieira is supported by the Beatrice Hunter Cancer Research Institute and the Nova Scotia Health Research Foundation, Renza Vento was partially funded by European Regional Development Fund, European Territorial Cooperation 2007–13 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–13) and grants from the Italian Ministry of Education, University and Research (MIUR) ex-60%, 2007; Riccardo Di Fiore was a recipient of fellowship granted by European Regional Development Fund, European Territorial Cooperation 2007–2013 (CCI 2007 CB 163 PO 037, OP Italia-Malta 2007–2013); Rita Dornetshuber-Fleiss was supported by the Austrian Science Fund (FWF, project number T 451-B18) and the Johanna Mahlke, geb.-Obermann-Stiftung; Roberta Palorini is supported by a SysBioNet fellowship; Roslida Abd Hamid is supported by the Ministry of Education, Malaysia-Exploratory Research Grant Scheme-Project no: ERGS/1-2013/5527165; Sabine A.S.Langie is the beneficiary of a postdoctoral grant from the AXA Research Fund and the Cefic-LRI Innovative Science Award 2013; Sakina Eltom is supported by NIH grant SC1CA153326; Samira A.Brooks was supported by National Research Service Award (T32 ES007126) from the National Institute of Environmental Health Sciences and the HHMI Translational Medicine Fellowship; Sandra Ryeom was supported by The Garrett B. Smith Foundation and the TedDriven Foundation; Thierry Massfelder was supported by the Institut National de la Santé et de la Recherche Médicale INSERM and Université de Strasbourg; Thomas Sanderson is supported by the Canadian Institutes of Health Research (CIHR; MOP-115019), the Natural Sciences and Engineering Council of Canada (NSERC; 313313) and the California Breast Cancer Research Program (CBCRP; 17UB-8703); Tiziana Guarnieri is supported by a grant from Fundamental Oriented Research (RFO) to the Alma Mater Studiorum University of Bologna, Bologna, Italy and thanks the Fondazione Cassa di Risparmio di Bologna and the Fondazione Banca del Monte di Bologna e Ravenna for supporting the Center for Applied Biomedical Research, S.Orsola-Malpighi University Hospital, Bologna, Italy; W.Kimryn Rathmell is supported by the V Foundation for Cancer Research and the American Cancer Society; William K.Decker was supported in part by grant RP110545 from the Cancer Prevention Research Institute of Texas; William H.Bisson was supported with funding from the NIH P30 ES000210; Yon Rojanasakul was supported with NIH grant R01-ES022968; Zhenbang Chen is supported by NIH grants (MD004038, CA163069 and MD007593); Zhiwei Hu is grateful for the grant support from an institutional start-up fund from The Ohio State University College of Medicine and The OSU James Comprehensive Cancer Center (OSUCCC) and a Seed Award from the OSUCCC Translational Therapeutics Program.
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- 2015
24. Improving performances of the knee replacement surgery process by applying DMAIC principles
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Alfonso Maria Ponsiglione, Giovanni Improta, Mario Cesarelli, Giovanni Balato, Liberatina Carmela Santillo, Mario Alessandro Russo, Eliana Raiola, Patrizia Cuccaro, Maria Romano, Improta, Giovanni, Balato, Giovanni, Romano, Maria, Ponsiglione, Alfonso Maria, Raiola, Eliana, Russo, MARIO ALESSANDRO, Cuccaro, Patrizia, Santillo, Liberatina Carmela, and Cesarelli, Mario
- Subjects
Male ,medicine.medical_specialty ,Quality management ,medicine.medical_treatment ,Cost-Benefit Analysis ,Interprofessional Relations ,Control (management) ,Knee replacement ,Efficiency, Organizational ,Hip replacement (animal) ,03 medical and health sciences ,0302 clinical medicine ,Brainstorming ,Health care ,medicine ,Humans ,030212 general & internal medicine ,appropriate health care ,Lean Six Sigma ,Arthroplasty, Replacement, Knee ,Aged ,Aged, 80 and over ,Patient Care Team ,business.industry ,030503 health policy & services ,Health Policy ,DMAIC cycle ,DMAIC ,Public Health, Environmental and Occupational Health ,Original Articles ,Length of Stay ,Middle Aged ,Quality Improvement ,Surgery ,Italy ,Female ,Original Article ,length of hospital stay ,0305 other medical science ,business ,delays and waiting list ,delays and waiting lists ,Total Quality Management ,quality management - Abstract
Rationale, Aims, and Objectives The work is a part of a project about the application of the Lean Six Sigma to improve health care processes. A previously published work regarding the hip replacement surgery has shown promising results. Here, we propose an application of the DMAIC (Define, Measure, Analyse, Improve, and Control) cycle to improve quality and reduce costs related to the prosthetic knee replacement surgery by decreasing patients' length of hospital stay (LOS) Methods The DMAIC cycle has been adopted to decrease the patients' LOS. The University Hospital “Federico II” of Naples, one of the most important university hospitals in Southern Italy, participated in this study. Data on 148 patients who underwent prosthetic knee replacement between 2010 and 2013 were used. Process mapping, statistical measures, brainstorming activities, and comparative analysis were performed to identify factors influencing LOS and improvement strategies. Results The study allowed the identification of variables influencing the prolongation of the LOS and the implementation of corrective actions to improve the process of care. The adopted actions reduced the LOS by 42%, from a mean value of 14.2 to 8.3 days (standard deviation also decreased from 5.2 to 2.3 days). Conclusions The DMAIC approach has proven to be a helpful strategy ensuring a significant decreasing of the LOS. Furthermore, through its implementation, a significant reduction of the average costs of hospital stay can be achieved. Such a versatile approach could be applied to improve a wide range of health care processes.
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- 2017
25. FKBP51s signature in peripheral blood mononuclear cells of melanoma patients as a possible predictive factor for immunotherapy
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Maria Romano, Vito Alessandro Lasorsa, Anna D'Angelillo, Simona Romano, Michele Russo, Nicola Zambrano, Mario Capasso, Paolo A. Ascierto, Ester Simeone, Paolo D'Arrigo, Romano, Simona, Simeone, Ester, D'Angelillo, Anna, D'Arrigo, Paolo, Russo, Michele, Capasso, Mario, Lasorsa, Vito Alessandro, Zambrano, Nicola, Ascierto, Paolo A, and Romano, MARIA FIAMMETTA
- Subjects
0301 basic medicine ,Male ,Cancer Research ,medicine.medical_treatment ,Immunology ,Ipilimumab ,Tregs ,Peripheral blood mononuclear cell ,Immunophenotyping ,Tacrolimus Binding Proteins ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Humans ,Melanoma ,Aged ,business.industry ,Immunotherapy ,medicine.disease ,Immune checkpoint ,030104 developmental biology ,FKBP5 ,Oncology ,030220 oncology & carcinogenesis ,Leukocytes, Mononuclear ,Female ,business ,Immunophenotype ,medicine.drug - Abstract
The inhibitory immune checkpoint PD-L1/PD1 promotes the alternative splicing of the FKBP5 gene, resulting in increased expression of its variant 4 in the peripheral blood mononuclear cells of melanoma patients. The variant 4 transcript is translated into the truncated FKBP51s protein. Given the importance of co-inhibitory signalling in tumour immune escape, here we tested the potential for using FKBP51s expression to predict immunotherapy outcomes. To do this, we immunophenotyped PBMCs from 118 melanoma patients and 77 age- and sex-matched healthy controls. Blood samples were collected before patients underwent ipilimumab treatment. In 64 of the 118 patients, FKBP51s expression was also assessed in regulatory T cells (Tregs). We found that each PBMC subset analysed contained an FKBP51s(pos) fraction, and that this fraction was greater in the melanoma patients than healthy controls. In CD4 T lymphocytes, the FKBP51s(neg) fraction was significantly impaired. Tregs count was increased in melanoma patients, which is in line with previous studies. Also, by analyses of FKBP51s in Tregs, we identified a subgroup of ipilimumab nonresponder patients (p = 0.002). In conclusion, FKBP51s-based immunophenotyping of melanoma patients revealed several profiles related to a negative immune regulatory control and identified an unknown Treg subset. These findings are likely to be useful in the selection of the patients that are candidate for immunotherapy.
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- 2017
26. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial
- Author
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Vaccaro, O, Masulli, M, Nicolucci, A, Bonora, E, Del Prato, S, Maggioni, Ap, Rivellese, Aa, Squatrito, S, Giorda, Cb, Sesti, G, Mocarelli, P, Lucisano, G, Sacco, M, Signorini, S, Cappellini, F, Perriello, G, Babini, Ac, Lapolla, A, Gregori, G, Giordano, C, Corsi, L, Buzzetti, R, Clemente, G, Di Cianni, G, Iannarelli, R, Cordera, R, La Macchia, O, Zamboni, C, Scaranna, C, Boemi, M, Iovine, C, Lauro, D, Leotta, S, Dall'Aglio, E, Cannarsa, E, Tonutti, L, Pugliese, G, Bossi, Ac, Anichini, R, Dotta, F, Di Benedetto, A, Citro, G, Antenucci, D, Ricci, L, Giorgino, F, Santini, C, Gnasso, A, De Cosmo, S, Zavaroni, D, Vedovato, M, Consoli, A, Calabrese, M, di Bartolo, P, Fornengo, P, Riccardi, G, IT) study group, Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA., Collaborators: Vaccaro O, Italian Diabetes Society., D'Angelo, F, Giansanti, R, Tanase, L, Lanari, L, Testa, I, Pancani, F, Ranchelli, A, Vagheggi, P, Scatona, A, Fontana, L, Laviola, L, Tarantino, L, Ippolito, C, Gigantelli, V, Manicone, M, Conte, E, Trevisan, R, Rota, R, Corsi, A, Dodesini, Ar, Reggiani, Gm, Montesi, L, Mazzella, N, Forlani, G, Caselli, C, Di Luzio, R, Mazzotti, A, Aiello, A, Barrea, A, Musto, A, D'Amico, F, Sinagra, T, Longhitano, S, Trowpea, V, Sparti, M, Italia, S, Lisi, E, Grasso, G, Pezzino, V, Insalaco, F, Carallo, C, Scicchitano, C, De Franceschi MS, Calbucci, G, Ripani, R, Cuneo, G, Corsi, S, Romeo, F, Lesina, A, Comoglio, M, Bonetto, C, Robusto, A, Nada, E, Asprino, V, Cetraro, R, Impieri, M, Lucchese, G, Donnarumma, G, Tizio, B, Lenza, L, Paraggio, P, Tomasi, F, Dozio, N, Scalambra, E, Mannucci, E, Lamanna, C, Cignarelli, M, Macchia, O, Fariello, S, Sorrentino, Mr, Franzetti, I, Radin, R, Annunziata, F, Bonabello, La, Durante, A, Dolcino, M, Gallo, F, Mazzucchelli, C, Aleo, A, Melga, P, Briatore, L, Maggi, D, Storace, D, Cecoli, F, D'Ugo, E, Pupillo, M, Baldassarre, Mpa, Salvati, F, Minnucci, A, De Luca, A, Zugaro, A, Santarelli, L, Bosco, A, Petrella, V, La Verghetta GG, De Gregorio, A, D'Andrea, S, Giuliani, Ae, Polidoro, Wl, Sperandio, A, Sciarretta, F, Pezzella, A, Carlone, A, Potenziani, S, Venditti, C, Foffi, C, Carbone, S, Cipolloni, L, Moretti, C, Leto, G, Serra, R, Petrachi, F, Romano, I, Lacaria, E, Russo, L, Goretti, C, Sannino, C, Dolci, M, Bruselli, L, Mori, Ml, Baccetti, F, Del Freo, M, Cucinotta, D, Giunta, L, Ruffo, Mc, Cannizzaro, D, Pintaudi, B, Perrone, G, Pata, P, Ragonese, F, Lettina, G, Mancuso, T, Coppolino, A, Piatti, Pm, Monti, L, Stuccillo, M, Lucotti, P, Setola, M, Crippa, Gv, Loi, C, Oldani, M, Bottalico, Ml, Pellegata, B, Bonomo, M, Menicatti, Lsm, Resi, V, Bertuzzi, F, Disoteo, Eo, Pizzi, G, Annuzzi, G, Capaldo, B, Nappo, R, Auciello, Sm, Turco, Aa, Costagliola, L, Corte, Gd, Vallefuoco, P, Nappi, F, Vitale, M, Cocozza, S, Ciano, O, Massimino, E, Garofalo, N, Avogaro, A, Guarneri, G, Fedele, D, Sartore, G, Chilelli, Nc, Burlina, S, Bonsembiante, B, Galluzzo, A, Torregrossa, V, Mancastroppa, G, Arsenio, L, Cioni, F, Caronna, S, Papi, M, Babini, M, Santeusanio, F, Calagreti, G, Timi, A, Tantucci, A, Marino, C, Ginestra, F, Di Biagio, R, Taraborelli, M, Miccoli, R, Bianchi, C, Garofolo, M, Politi, Ks, Penno, G, Livraga, S, Calzoni, F, Mancastroppa, Glf, Corsini, E, Tedeschi, A, Gaglianò, Ms, Ippolito, G, Salutini, E, Cervellino, F, Natale, M, Salvatore, V, Zampino, A, Sinisi, R, Arcangeli, A, Zogheri, A, Guizzotti, S, Longo, R, Di Bartolo, P, Pellicano, F, Scolozzi, P, Termine, S, Luberto, A, Ballardini, G, Trojani, C, Mazzuca, P, Bruglia, M, Ciamei, M, Genghini, S, Zannoni, C, Rangel, G, Salvi, L, Zappaterreno, A, Cordone, S, Simonelli, P, Meggiorini, M, Frasheri, A, Di Pippo, C, Maglio, C, Mazzitelli, G, Rinaldi, Me, Galli, A, Romano, M, D'Angelo, P, Suraci, C, Bacci, S, Palena, Ap, Genovese, S, Mancino, M, Rondinelli, M, Capone, F, Calabretto, E, Bulgheroni, M, Bucciarelli, L, Ceccarelli, E, Fondelli, C, Santacroce, C, Guarino, E, Nigi, L, Lalli, C, Di Vizia, G, Scarponi, M, Montani, V, Di Bernardino, P, Romagni, P, Dolcetti, K, Forte, E, Tamburo, L, Perin, Pc, Prinzis, T, Gruden, G, Bruno, G, Zucco, C, Perotta, M, Marena, S, Monsignore, S, Panero, F, Ponzi, F, Carpinteri, R, Casagrande, Ml, Coletti, Mf, Balini, A, Filopanti, M, Madaschi, S, Pulcina, A, Grimaldi, F, Venturini, G, Agus, S, Pagnutti, S, Guidotti, F, Cavarape, A, Cigolini, M, Pichiri, I, Brangani, C, Fainelli, G, Tomasetto, E, Zoppini, G, Galletti, A, Perrone, D, Capra, C, Bianchini, F, Ceseri, M, Di Nardo, B, Sasso, E, Bartolomei, B, Suliman, I, Fabbri, G, Romano, G, Maturo, N, Nunziata, G, Capobianco, G, De Simone, G, Villa, V, Rota, G, Pentangelo, C, Carbonara, O, Caiazzo, G, Cutolo, M, Sorrentino, T, Mastrilli, V, Amelia, U, Masi, S, Corigliano, G, Gaeta, I, Armentano, V, Calatola, P, Capuano, G, Angiulli, B, Auletta, P, Petraroli, E, Iodice, Ce, Agrusta, M., Vaccaro, Olga, Masulli, Maria, Nicolucci, Antonio, Bonora, Enzo, Del Prato, Stefano, Maggioni, Aldo P, Rivellese, Angela A, Squatrito, Sebastiano, Giorda, Carlo B, Sesti, Giorgio, Mocarelli, Paolo, Lucisano, Giuseppe, Sacco, Michele, Signorini, Stefano, Cappellini, Fabrizio, Perriello, Gabriele, Babini, Anna Carla, Lapolla, Annunziata, Gregori, Giovanna, Giordano, Carla, Corsi, Laura, Buzzetti, Raffaella, Clemente, Gennaro, Di Cianni, Graziano, Iannarelli, Rossella, Cordera, Renzo, La Macchia, Olga, Zamboni, Chiara, Scaranna, Cristiana, Boemi, Massimo, Iovine, Ciro, Lauro, Davide, Leotta, Sergio, Dall'Aglio, Elisabetta, Cannarsa, Emanuela, Tonutti, Laura, Pugliese, Giuseppe, Bossi, Antonio C, Anichini, Roberto, Dotta, Francesco, Di Benedetto, Antonino, Citro, Giuseppe, Antenucci, Daniela, Ricci, Lucia, Giorgino, Francesco, Santini, Costanza, Gnasso, Agostino, De Cosmo, Salvatore, Zavaroni, Donatella, Vedovato, Monica, Consoli, Agostino, Calabrese, Maria, Di Bartolo, Paolo, Fornengo, Paolo, Riccardi, Gabriele, Maggioni, Aldo Pietro, D'Angelo, Federica, Giansanti, Roberto, Tanase, Laura, Lanari, Luigi, Testa, Ivano, Pancani, Francesca, Ranchelli, Anna, Vagheggi, Paolo, Scatona, Alessia, Fontana, Lucia, Laviola, Luigi, Tarantino, Lucia, Ippolito, Claudia, Gigantelli, Vittoria, Manicone, Mariangela, Conte, Eleonora, Trevisan, Roberto, Rota, Rossella, Corsi, Anna, Dodesini, Alessandro R., Reggiani, Giulio Marchesini, Montesi, Luca, Mazzella, Natalia, Forlani, Gabriele, Caselli, Chiara, Di Luzio, Raffaella, Mazzotti, Arianna, Aiello, Antimo, Barrea, Angelina, Musto, Antonio, D'Amico, Fiorentina, Sinagra, Tiziana, Longhitano, Sara, Trowpea, Vanessa, Sparti, Maria, Italia, Salvatore, Lisi, Enrico, Grasso, Giuseppe, Pezzino, Vincenzo, Insalaco, Federica, Carallo, Claudio, Scicchitano, Caterina, De Franceschi, Maria Serena, Calbucci, Giovanni, Ripani, Raffaella, Cuneo, Giacomo, Corsi, Simona, Giorda, Carlo B., Romeo, Francesco, Lesina, Annalisa, Comoglio, Marco, Bonetto, Caterina, Robusto, Anna, Nada, Elisa, Asprino, Vincenzo, Cetraro, Rosa, Impieri, Michelina, Lucchese, Giuseppe, Donnarumma, Giovanna, Tizio, Biagio, Lenza, Lazzaro, Paraggio, Pia, Tomasi, Franco, Dozio, Nicoletta, Scalambra, Egle, Mannucci, Edoardo, Lamanna, Caterina, Cignarelli, Mauro, Macchia, Olga La, Fariello, Stefania, Sorrentino, Maria Rosaria, Franzetti, Ivano, Radin, Raffaella, Annunziata, Francesca, Bonabello, Laura Affinito, Durante, Arianna, Dolcino, Mara, Gallo, Fiorenza, Mazzucchelli, Chiara, Aleo, Anna, Melga, Pierluigi, Briatore, Lucia, Maggi, Davide, Storace, Daniela, Cecoli, Francesca, D'Ugo, Ercole, Pupillo, Mario, Baldassarre, Maria Pompea Antonia, Salvati, Filippo, Minnucci, Anita, De Luca, Angelo, Zugaro, Antonella, Santarelli, Livia, Bosco, Angela, Petrella, Vittorio, La Verghetta, Grazia Giovanna, De Gregorio, Antonella, D'Andrea, Settimio, Giuliani, Anna Elisa, Polidoro, W. Lorella, Sperandio, Alessandra, Sciarretta, Filomena, Pezzella, Alfonso, Carlone, Angela, Potenziani, Stella, Venditti, Chiara, Foffi, Chiara, Carbone, Salvatore, Cipolloni, Laura, Moretti, Chiara, Leto, Gaetano, Serra, Rosalia, Petrachi, Francesca, Romano, Isabella, Lacaria, Emilia, Russo, Laura, Goretti, Chiara, Sannino, Claudia, Dolci, Maria, Bruselli, Laura, Mori, Mary L., Baccetti, Fabio, Del Freo, Maria, Cucinotta, Domenico, Giunta, Loretta, Ruffo, Maria Concetta, Cannizzaro, Desiree, Pintaudi, Basilio, Perrone, Giovanni, Pata, Pietro, Ragonese, Francesco, Lettina, Gabriele, Mancuso, Teresa, Coppolino, Aldo, Piatti, Pier Marco, Monti, Lucilla, Stuccillo, Michela, Lucotti, Pietro, Setola, Manuela, Crippa, Giulia Valentina, Loi, Cinzia, Oldani, Matteo, Bottalico, Maria Luisa, Pellegata, Beatrice, Bonomo, Matteo, Menicatti, Laura Silvia Maria, Resi, Veronica, Bertuzzi, Federico, Disoteo, Eugenia Olga, Pizzi, Gianluigi, Rivellese, Angela Albarosa, Annuzzi, Giovanni, Capaldo, Brunella, Nappo, Rossella, Auciello, Stefania Michela, Turco, Anna Amelia, Costagliola, Lucia, Corte, Giuseppina Della, Vallefuoco, Pasquale, Nappi, Francesca, Vitale, Marilena, Cocozza, Sara, Ciano, Ornella, Massimino, Elena, Garofalo, Nadia, Avogaro, Angelo, Guarneri, Gabriella, Fedele, Domenico, Sartor, Giovanni, Chilelli, Nino Cristiano, Burlina, Silvia, Bonsembiante, Barbara, Galluzzo, Aldo, Torregrossa, Vittoria, Mancastroppa, Giovanni, Arsenio, Leone, Cioni, Federico, Caronna, Silvana, Papi, Matteo, Babini, Massimiliano, Santeusanio, Fausto, Calagreti, Gioia, Timi, Alessia, Tantucci, Alice, Marino, Cecilia, Ginestra, Federica, Di Biagio, Rosamaria, Taraborelli, Merilda, Miccoli, Roberto, Bianchi, Cristina, Garofolo, Monia, Politi, Konstantina Savina, Penno, Giuseppe, Livraga, Stefania, Calzoni, Fabio, Mancastroppa, Giovanni Luigi Francesco, Corsini, Elisa, Tedeschi, Anna, Gaglianã², Maria Sole, Ippolito, Giulio, Salutini, Elisabetta, Cervellino, Francesco, Natale, Maria, Salvatore, Vita, Zampino, Armando, Sinisi, Rosa, Arcangeli, Adolfo, Zogheri, Alessia, Guizzotti, Sandra, Longo, Rossella, Pellicano, Francesca, Scolozzi, Patrizia, Termine, Simona, Luberto, Alessandra, Ballardini, Giorgio, Trojani, Cristina, Mazzuca, Paolo, Bruglia, Matteo, Ciamei, Monica, Genghini, Silvia, Zannoni, Chiara, Vitale, Martina, Rangel, Graziela, Salvi, Laura, Zappaterreno, Alessandra, Cordone, Samantha, Simonelli, Paola, Meggiorini, Marilla, Frasheri, Aurora, Di Pippo, Clelia, Maglio, Cristina, Mazzitelli, Giulia, Rinaldi, Maria Elena, Galli, Angelica, Romano, Maria, D'Angelo, Paola, Suraci, Concetta, Bacci, Simonetta, Palena, Antonio Pio, Genovese, Stefano, Mancino, Monica, Rondinelli, Maurizio, Capone, Filippo, Calabretto, Elisabetta, Bulgheroni, Monica, Bucciarelli, Loredana, Ceccarelli, Elena, Fondelli, Cecilia, Santacroce, Clorinda, Guarino, Elisa, Nigi, Laura, Lalli, Carlo, Di Vizia, Giovanni, Scarponi, Maura, Montani, Valeria, Di Bernardino, Paolo, Romagni, Paola, Dolcetti, Katia, Forte, Elisa, Tamburo, Lucilla, Perin, Paolo Cavallo, Prinzis, Tania, Gruden, Gabriella, Bruno, Graziella, Zucco, Chiara, Perotta, Massimo, Marena, Saverio, Monsignore, Simona, Panero, Francesco, Ponzi, Fulvia, Bossi, Antonio Carlo, Carpinteri, Rita, Casagrande, Maria Linda, Coletti, Maria Francesca, Balini, Annalisa, Filopanti, Marcello, Madaschi, Sara, Pulcina, Anna, Grimaldi, Franco, Venturini, Giorgio, Agus, Sandra, Pagnutti, Stefania, Guidotti, Francesca, Cavarape, Alessandro, Cigolini, Massimo, Pichiri, Isabella, Brangani, Corinna, Fainelli, Giulia, Tomasetto, Elena, Zoppini, Giacomo, Galletti, Anna, Perrone, Dominica, Capra, Claudio, Bianchini, Francesca, Ceseri, Martina, Di Nardo, Barbara, Sasso, Elisa, Bartolomei, Barbara, Suliman, Irina, Fabbri, Gianna, Romano, Geremia, Maturo, Nicola, Nunziata, Giuseppe, Capobianco, Giuseppe, De Simone, Giuseppina, Villa, Valeria, Rota, Giuseppe, Pentangelo, Carmine, Carbonara, Ornella, Caiazzo, Gennaro, Cutolo, Michele, Sorrentino, Tommasina, Mastrilli, Valeria, Amelia, Umberto, Masi, Stefano, Corigliano, Gerardo, Gaeta, Iole, Armentano, Vincenzo, Calatola, Pasqualino, Capuano, Gelsomina, Angiulli, Bruno, Auletta, Pasquale, Petraroli, Ettore, Iodice, Cinzia E., Agrusta, Mariano, Vaccaro, O, Masulli, M, Nicolucci, A, Bonora, E, Del Prato, S, Maggioni, A, Rivellese, A, Squatrito, S, Giorda, C, Sesti, G, Mocarelli, P, Lucisano, G, Sacco, M, Signorini, S, Cappellini, F, Perriello, G, Babini, A, Lapolla, A, Gregori, G, Giordano, C, Corsi, L, Buzzetti, R, Clemente, G, Di Cianni, G, Iannarelli, R, Cordera, R, La Macchia, O, Zamboni, C, Scaranna, C, Boemi, M, Iovine, C, Lauro, D, Leotta, S, Dall'Aglio, E, Cannarsa, E, Tonutti, L, Pugliese, G, Bossi, A, Anichini, R, Dotta, F, Di Benedetto, A, Citro, G, Antenucci, D, Ricci, L, Giorgino, F, Santini, C, Gnasso, A, De Cosmo, S, Zavaroni, D, Vedovato, M, Consoli, A, Calabrese, M, di Bartolo, P, Fornengo, P, Riccardi, G, D'Angelo, F, Giansanti, R, Tanase, L, Lanari, L, Testa, I, Pancani, F, Ranchelli, A, Vagheggi, P, Scatona, A, Fontana, L, Laviola, L, Tarantino, L, Ippolito, C, Gigantelli, V, Manicone, M, Conte, E, Trevisan, R, Rota, R, Dodesini, A, Reggiani, G, Montesi, L, Mazzella, N, Forlani, G, Caselli, C, Di Luzio, R, Mazzotti, A, Aiello, A, Barrea, A, Musto, A, D'Amico, F, Sinagra, T, Longhitano, S, Trowpea, V, Sparti, M, Italia, S, Lisi, E, Grasso, G, Pezzino, V, Insalaco, F, Carallo, C, Scicchitano, C, De Franceschi, M, Calbucci, G, Ripani, R, Cuneo, G, Corsi, S, Romeo, F, Lesina, A, Comoglio, M, Bonetto, C, Robusto, A, Nada, E, Asprino, V, Cetraro, R, Impieri, M, Lucchese, G, Donnarumma, G, Tizio, B, Lenza, L, Paraggio, P, Tomasi, F, Dozio, N, Scalambra, E, Mannucci, E, Lamanna, C, Cignarelli, M, Macchia, O, Fariello, S, Sorrentino, M, Franzetti, I, Radin, R, Annunziata, F, Bonabello, L, Durante, A, Dolcino, M, Gallo, F, Mazzucchelli, C, Aleo, A, Melga, P, Briatore, L, Maggi, D, Storace, D, Cecoli, F, D'Ugo, E, Pupillo, M, Baldassarre, M, Salvati, F, Minnucci, A, De Luca, A, Zugaro, A, Santarelli, L, Bosco, A, Petrella, V, La Verghetta, G, D'Andrea, S, Giuliani, A, Polidoro, W, Sperandio, A, Sciarretta, F, Pezzella, A, Carlone, A, Potenziani, S, Venditti, C, Foffi, C, Carbone, S, Cipolloni, L, Moretti, C, Leto, G, Serra, R, Petrachi, F, Romano, I, Lacaria, E, Russo, L, Goretti, C, Sannino, C, Dolci, M, Bruselli, L, Mori, M, Baccetti, F, Del Freo, M, Cucinotta, D, Giunta, L, Ruffo, M, Cannizzaro, D, Pintaudi, B, Perrone, G, Pata, P, Ragonese, F, Lettina, G, Mancuso, T, Coppolino, A, Piatti, P, Monti, L, Stuccillo, M, Lucotti, P, Setola, M, Crippa, G, Loi, C, Oldani, M, Bottalico, M, Pellegata, B, Bonomo, M, Menicatti, L, Resi, V, Bertuzzi, F, Disoteo, E, Pizzi, G, Annuzzi, G, Capaldo, B, Nappo, R, Auciello, S, Turco, A, Costagliola, L, Corte, G, Vallefuoco, P, Nappi, F, Vitale, M, Cocozza, S, Ciano, O, Massimino, E, Garofalo, N, Avogaro, A, Guarneri, G, Fedele, D, Sartore, G, Chilelli, N, Burlina, S, Bonsembiante, B, Galluzzo, A, Torregrossa, V, Mancastroppa, G, Arsenio, L, Cioni, F, Caronna, S, Papi, M, Santeusanio, F, Calagreti, G, Timi, A, Tantucci, A, Marino, C, Ginestra, F, Di Biagio, R, Taraborelli, M, Miccoli, R, Bianchi, C, Garofolo, M, Politi, K, Penno, G, Livraga, S, Calzoni, F, Corsini, E, Tedeschi, A, Gagliano, M, Ippolito, G, Salutini, E, Cervellino, F, Natale, M, Salvatore, V, Zampino, A, Sinisi, R, Arcangeli, A, Zogheri, A, Guizzotti, S, Longo, R, Pellicano, F, Scolozzi, P, Termine, S, Luberto, A, Ballardini, G, Trojani, C, Mazzuca, P, Bruglia, M, Ciamei, M, Genghini, S, Zannoni, C, Rangel, G, Salvi, L, Zappaterreno, A, Cordone, S, Simonelli, P, Meggiorini, M, Frasheri, A, Di Pippo, C, Maglio, C, Mazzitelli, G, Rinaldi, M, Galli, A, Romano, M, D'Angelo, P, Suraci, C, Bacci, S, Palena, A, Genovese, S, Mancino, M, Rondinelli, M, Capone, F, Calabretto, E, Bulgheroni, M, Bucciarelli, L, Ceccarelli, E, Fondelli, C, Santacroce, C, Guarino, E, Nigi, L, Lalli, C, Di Vizia, G, Scarponi, M, Montani, V, Di Bernardino, P, Romagni, P, Dolcetti, K, Forte, E, Tamburo, L, Perin, P, Prinzis, T, Gruden, G, Bruno, G, Zucco, C, Perotta, M, Marena, S, Monsignore, S, Panero, F, Ponzi, F, Carpinteri, R, Casagrande, M, Coletti, M, Balini, A, Filopanti, M, Madaschi, S, Pulcina, A, Grimaldi, F, Venturini, G, Agus, S, Pagnutti, S, Guidotti, F, Cavarape, A, Cigolini, M, Pichiri, I, Brangani, C, Fainelli, G, Tomasetto, E, Zoppini, G, Galletti, A, Perrone, D, Capra, C, Bianchini, F, Ceseri, M, Di Nardo, B, Sasso, E, Bartolomei, B, Suliman, I, Fabbri, G, Romano, G, Maturo, N, Nunziata, G, Capobianco, G, De Simone, G, Villa, V, Rota, G, Pentangelo, C, Carbonara, O, Caiazzo, G, Cutolo, M, Sorrentino, T, Mastrilli, V, Amelia, U, Masi, S, Corigliano, G, Gaeta, I, Armentano, V, Calatola, P, Capuano, G, Angiulli, B, Auletta, P, Petraroli, E, Iodice, C, Agrusta, M, di Bartolo, Paolo, Polidoro, w Lorella, Sartore, Giovanni, and Gaglianò, Maria Sole
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Male ,Diabetes and Metabolism, ipoglycemic drugs, cardiovascualr event ,Settore MED/09 - Medicina Interna ,endocrine system diseases ,IMPACT ,pioglitazone versus sulfonylureas ,Endocrinology, Diabetes and Metabolism ,GLIMEPIRIDE ,Diabetes, cardiovascular events, metformin, pioglitazone, sulphonylureas ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Internal Medicine ,Endocrinology ,law.invention ,Settore MED/13 - Endocrinologia ,Glibenclamide ,0302 clinical medicine ,Randomized controlled trial ,law ,GLYCEMIC CONTROL ,Gliclazide ,Internal medicine ,diabetes and metabolism ,RISK ,education.field_of_study ,diabetes ,Incidence ,endocrinology, diabetes and metabolism ,endocrinology ,Middle Aged ,INSULIN ,Metformin ,Treatment Outcome ,Editorial ,sulphonylureas ,Cardiovascular Diseases ,Combination ,Drug Therapy, Combination ,Female ,Type 2 ,medicine.drug ,medicine.medical_specialty ,Population ,030209 endocrinology & metabolism ,Aged ,Diabetes Mellitus, Type 2 ,Humans ,Hypoglycemic Agents ,Pioglitazone ,Sulfonylurea Compounds ,Thiazolidinediones ,Cardiovascular events ,03 medical and health sciences ,GLUCOSE-LOWERING DRUGS ,Drug Therapy ,Diabetes Mellitus ,medicine ,sulfonylureas ,education ,TOSCA.IT ,business.industry ,MORTALITY ,nutritional and metabolic diseases ,Insulin resistance ,medicine.disease ,Surgery ,Glimepiride ,business ,FOLLOW-UP - Abstract
Background The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. Methods TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50â75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2â3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15â45 mg) or a sulfonylurea (5â15 mg glibenclamide, 2â6 mg glimepiride, or 30â120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. Findings Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74â1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p
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- 2017
27. FKBP51 immunohistochemical expression: A new prognostic biomarker for OSCC?
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Maria Fiammetta Romano, Massimo Mascolo, Gennaro Ilardi, Luigi Califano, Virginia Napolitano, Simona Romano, Loredana Postiglione, Daniela Russo, Giovanni Orabona Dell’Aversana, Stefania Staibano, Angela Celetti, Pierpaolo Di Lorenzo, Silvia Varricchio, Francesco Merolla, F Astarita, Russo, Daniela, Merolla, Francesco, Mascolo, Massimo, Ilardi, Gennaro, Romano, Simona, Varricchio, Silvia, Napolitano, Virginia, Celetti, Angela, Postiglione, Loredana, DI LORENZO, Pierpaolo, Califano, Luigi, DELL'AVERSANA ORABONA, Giovanni, Astarita, Fabio, Romano, MARIA FIAMMETTA, and Staibano, Stefania
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0301 basic medicine ,Oncology ,Male ,Pathology ,Bayes theorem ,medicine.medical_treatment ,Gene Expression ,Kaplan-Meier Estimate ,Pathogenesis ,lcsh:Chemistry ,0302 clinical medicine ,Squamous cell carcinoma ,lcsh:QH301-705.5 ,Spectroscopy ,Aged, 80 and over ,Human papillomavirus 16 ,Oral cancer ,Computer Science Applications1707 Computer Vision and Pattern Recognition ,General Medicine ,Middle Aged ,FKBP51 ,Immunotherapy ,Prognosis ,Catalysis ,Molecular Biology ,Physical and Theoretical Chemistry ,Organic Chemistry ,Inorganic Chemistry ,Immunohistochemistry ,Computer Science Applications ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Lymphatic Metastasis ,Carcinoma, Squamous Cell ,Female ,Mouth Neoplasms ,prognosi ,Adult ,medicine.medical_specialty ,In situ hybridization ,Article ,Tacrolimus Binding Proteins ,03 medical and health sciences ,Immune system ,Tongue ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Cyclin-Dependent Kinase Inhibitor p16 ,Aged ,Neoplasm Staging ,Chemotherapy ,business.industry ,Radiation therapy ,stomatognathic diseases ,oral cancer ,prognosis ,immunotherapy ,squamous cell carcinoma ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cutaneous melanoma ,Neoplasm Grading ,business - Abstract
Up-to-date, several molecular markers of prognosis have been studied in Oral Squamous Cell Carcinoma (OSCC), but none entered in the clinical setting. Therapy of OSCC tumors mainly relies on surgery, radiotherapy and partially on chemotherapy; there is an urgent need for biomarkers able to better stratify OSCC patients’ risk to address targeted therapeutic strategies. The role of immune response in the pathogenesis and biological behavior of OSCC has been investigated by several authors, and promising results have been obtained with immune checkpoint inhibitors. We already investigated the role of the immune modulator FK506-binding protein 51 (FKBP51), a FK506-binding immunophilin, in cutaneous melanoma biology, and its expression in several human solid tumors. In the present study, we aimed to assess the value of FKBP51 expression in OSCC tumor cells as a marker of outcome. We collected clinical data from 72 patients who underwent surgery for Squamous Cell Carcinoma (SCC) of the tongue, floor, lips and palate. FKBP51 expression was assessed by immunohistochemistry on paraffin-embedded tumor tissues. In addition, we evaluated the human papillomavirus (HPV) status of primary tumors by immunohistochemistry, viral subtyping and In Situ Hybridization (ISH) assay. We found that high FKBP51-expressing tumors characterized the OSCCs with the worst prognosis: the high immunohistochemical expression of FKBP51 associated with death occurring within five years from the diagnosis with a sensitivity of 88.46% and a specificity of 91.67%. The estimated positive predictive value of the test was 88.45% and negative predictive value 91.67%. We tested FKBP51 mRNA presence, by RT-PCR assay, in a selected series of OSCC tumors, and we found that mRNA correlated well to the protein expression and to the clinical outcome. Applying the Bayes formula, we estimated an 88% probability of dying within five years from the diagnosis of OSCC patients with a high FKBP51 immunohistochemical (IHC) test result (>51% of FKBP51 positive tumor cells). On the basis of our analysis, we propose tumor tissue expression of FKBP51 protein as a reliable prognostic marker for OSCC tumors.
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- 2017
28. Tirofiban induces VEGF production and stimulates migration and proliferation of endothelial cells
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Simona Romano, Paolo D'Arrigo, Michele Polimeno, Stefano Messina, Paolo Ferraro, Nicola Corcione, Anna D'Angelillo, Maria Fiammetta Romano, Rita Bisogni, Paolo Pepino, Arturo Giordano, Giordano, A, D'Angelillo, Anna, Romano, Simona, D'Arrigo, P, Corcione, N, Bisogni, Rita, Messina, S, Polimeno, M, Pepino, P, Ferraro, P, and Romano, MARIA FIAMMETTA
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Vascular Endothelial Growth Factor A ,Endothelium ,Physiology ,Fibrinogen receptor ,Proliferation ,Umbilical vein ,Endothelial ,Fibrinolytic Agents ,Cell Movement ,Human Umbilical Vein Endothelial Cells ,Humans ,Medicine ,Aorta ,Cells, Cultured ,Migration ,Cell Proliferation ,Pharmacology ,business.industry ,Cell growth ,Endothelial Cells ,Cell migration ,Tirofiban ,medicine.anatomical_structure ,Gene Expression Regulation ,Immunology ,cardiovascular system ,Cancer research ,Tyrosine ,Molecular Medicine ,Endothelium, Vascular ,GPIIb/IIIa ,business ,Wound healing ,Ex vivo ,medicine.drug - Abstract
Tirofiban is a fibrinogen receptor antagonist, generated using the tripeptide Arg-Gly-Asp (RGD) as a template. RGD activates integrin receptors and integrin-mediated signals are necessary for normal cells to promote survival and stimulate cell cycle progression. We investigated whether tirofiban activated growth-stimulatory signals in endothelium. For this study human umbilical vein endothelial cells (HUVEC) and human aortic endothelial cells (HAEC) were used. Analysis of cell proliferation, by cell counts, showed that the number of endothelial cells doubled after 72 h of culture in the absence of tirofiban, while they were tripled and even quadrupled, in the presence of increasing doses of the drug. Moreover, tirofiban-stimulated cells had a greater ability to migrate through the transwell filters of Boyden chamber, compared to unstimulated cells. The scratch assay, which mimics cell migration during wound healing, showed that tirofiban stimulated HUVECs to migrate into the leading hedge of the scratch. Western blot showed that tirofiban increased the expression levels of VEGF and the downstream effectors Erk and cyclin D. An inhibitor of VEGFR2 counteracted tirofiban-induced-proliferation, suggesting a role for VEGF in such effect. Our study shows that tirofiban stimulates the migration and proliferation of endothelial cells suggesting that it can promote endothelial repair. Ex vivo cultures of arterial rings confirmed the growth stimulatory effect of tirofiban on endothelium. Thus, the benefits of tirofiban in those with acute coronary syndromes undergoing PTCA may be due to rapid endothelization of damaged vessel, besides antiplatelet effects.
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- 2014
29. Cellular and Molecular Background Underlying the Diversity in Therapeutic Responses Between Primary Tumours and Metastases
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Maria Romano, Anna D'Angelillo, Alfredo Romano, Giovanna Nappo, Simona Romano, Romano, Simona, D'Angelillo, Anna, Romano, A, Nappo, G, and Romano, MARIA FIAMMETTA
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Pathology ,medicine.medical_specialty ,Growth control ,Biochemistry ,Benign tumours ,Metastatic tumours ,Metastasis ,Cell Movement ,Neoplasms ,Drug Discovery ,medicine ,Animals ,Humans ,Cell Lineage ,Neoplasm Metastasis ,Treatment resistance ,Pharmacology ,business.industry ,Organic Chemistry ,Cancer ,medicine.disease ,Lymphatic system ,Cancer cell ,Disease Progression ,Neoplastic Stem Cells ,Cancer research ,Molecular Medicine ,business - Abstract
Metastasis, also called secondary neoplastic disease, is a tumour newly formed in a site different from that of origin, as a consequence of cancer progression and dissemination largely through blood and lymphatic vessels. The ability to form metastases is the main property that distinguishes malignant from benign tumours. Treatments for metastatic cancer are similar in practice to those for primary tumours, but such treatments are mostly palliative; indeed, almost all deaths caused by solid tumours occur in the metastatic phase. Increasing evidence supports the concept that therapies for primary tumours are inadequate to treat metastasis and can even promote formation of metastases, while exerting local growth control. Furthermore, recurrent tumours, which are denoted by increased aggressiveness and therapy resistance in comparison with the primary tumour, have an increased metastatic potential. Genetic modifications occurring during tumour progression lead to substantial differences between the primary and metastatic tumours. This emphasises the importance of designing novel therapies for metastasis. In the last decade, a number of studies have contributed to the understanding of the genetic rearrangements underlying the conversion of cancer cells into the metastasis founder cells. The present article aims at reviewing recent advances in metastasis research and attempts to discuss the reasons for which the therapeutic strategies against primary tumours may not satisfactorily address their metastatic counterparts.
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- 2014
30. Comparison of Biolimus Versus Everolimus for Drug-Eluting Stents in the Percutaneous Treatment of Infra-Inguinal Arterial Disease
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Antonino G.M. Marullo, Gennaro Maresca, Nicola Corcione, Maria Romano, Gabriele Giordano, Raffaella Avellino, Enrico Coscioni, Stefano Messina, Giuseppe Biondi-Zoccai, Arturo Giordano, Paolo Ferraro, Mariangela Peruzzi, Giovanni Napolitano, Giordano, Arturo, Ferraro, Paolo, Corcione, Nicola, Messina, Stefano, Maresca, Gennaro, Coscioni, Enrico, Avellino, Raffaella, Giordano, Gabriele, Peruzzi, Mariangela, Marullo, Antonino G. M., Napolitano, Giovanni, Romano, Maria Fiammetta, and Biondi-Zoccai, Giuseppe
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Male ,Comparative Effectiveness Research ,Time Factors ,medicine.medical_treatment ,Superficial femoral artery ,Biolimu ,chemistry.chemical_compound ,Restenosis ,Retrospective Studie ,Stent ,Drug-Eluting Stent ,Sirolimu ,Amputation ,Aged, 80 and over ,Hazard ratio ,Endovascular Procedures ,Drug-Eluting Stents ,Middle Aged ,Limb Salvage ,Everolimu ,Treatment Outcome ,Drug-eluting stent ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Human ,medicine.medical_specialty ,Time Factor ,Popliteal artery ,Revascularization ,Prosthesis Design ,Amputation, Surgical ,Peripheral Arterial Disease ,Internal medicine ,Umirolimus ,medicine ,Humans ,Everolimus ,Aged ,Retrospective Studies ,Pharmacology ,Sirolimus ,Endovascular Procedure ,Peripheral artery disease ,business.industry ,Cardiovascular Agents ,medicine.disease ,Surgery ,chemistry ,Cardiovascular Agent ,Umirolimu ,business - Abstract
Background: Drug-eluting stents (DES) are now considered the most promising device to treat peripheral artery disease (PAD) and minimize restenosis. There is uncertainty however on the best antirestenotic drug for such devices. In particular, biolimus (i.e. umirolimus) and everolimus are two of the most promising agents, given the extensive data in support of their coronary safety and efficacy, but their comparative effectiveness for peripheral interventions is not established. Methods: Building upon our extensive experience in the percutaneous treatment of infra-inguinal artery disease with DES, we compared the acute and longterm outlook of patients treated with biolimus-eluting stents (BES) and everolimus-eluting stents (EES). We collected baseline, procedural and outcome details on all patients undergoing infra-inguinal BES or EES implantation. The endpoints of interest were death, amputation, revascularization, their composite, and change in Fontaine class. A total of 80 patients were included (20 treated with BES and 60 with EES). Most features were similar in the two groups, despite longer lesions in the EES group. Unadjusted analysis showed similar results irrespective of the drug used, with composite endpoint occurring, respectively, in 4 (20.0%) and 10 (16.7%) (p=0.741). Results and Conclusion: However, analysis with inverse probability of treatment weighting showed significant differences in the risk of revascularization (hazard ratio of BES vs EES=9.55 [95% confidence interval 2.16-42.23], p=0.003) and composite endpoint (hazard ratio=5.11 [1.33-19.62], p=0.018). In conclusion, EES appear superior to BES for endovascular therapy of infrainguinal artery disease. Dedicated randomized trials are required to definitely confirm or disprove these findings.
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- 2016
31. Bioengineering activities in proprioceptive and robotic rehabilitation at Salvatore Maugeri Foundation
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Luigi Iuppariello, Paolo Bifulco, Mario Cesarelli, Giovanni D'Addio, Maria Romano, Cesarelli, Mario, Iuppariello, Luigi, Romano, Maria, Bifulco, Paolo, and D'Addio, Giovanni
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Protocol (science) ,medicine.medical_specialty ,Decision support system ,Engineering ,Rehabilitation ,Reaching movement ,Proprioception ,business.industry ,Regent suit ,Renewable Energy, Sustainability and the Environment ,medicine.medical_treatment ,Biomedical Engineering ,Foundation (evidence) ,Energy Engineering and Power Technology ,Robotic rehabilitation ,Rehabilitation outcome ,Gait (human) ,Physical medicine and rehabilitation ,medicine ,Rehabilation ,Submovement ,business ,Gaussian mixture ,Simulation - Abstract
Over the last decades, numerous and extensive research programs have been conducted in the field of robotic and proprioceptive rehabilitation. Robotic rehabilitation allows to record quantitative data about movement patterns that can help clinicians to better address the rehabilitation protocols providing information not captured using clinical measures, but the biome-chanical parameters proposed until today, to evaluate the quality of the movement are not yet standardized. Equally, the proprioception rehabilitation is known to play important roles in the planning and control of limb posture and movement. The Russian Academy of Sciences has recently developed the "Regent Suit" (RS), an experimental medical device derived from a suit worn by astronauts for therapeutical purposes after space flights. Although preliminary studies describe rehabilitation outcome of the RS in stroke, EMG changes induced by the suit are not known. The purpose of this paper is to review the rehabilitation activities employed at Salvatore Maugeri Foundation in the last two years, showing the main robotic and proprioceptive rehabilitation protocol developed to carefully analyse the motor strategies of the movement and of the gait in pathological conditions.
- Published
- 2016
32. Simulation of foetal phonocardiographic recordings for testing of FHR extraction algorithms
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Mario Cesarelli, Maria Romano, Paolo Bifulco, Mariano Ruffo, Cesarelli, Mario, Ruffo, M., Romano, Maria, and Bifulco, Paolo
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Time Factors ,Cardiotocography ,Computer science ,Pregnancy Trimester, Third ,Normal Distribution ,Foetal heart sounds ,Pilot Projects ,Health Informatics ,Pregnancy ,medicine ,Humans ,Computer Simulation ,medicine.diagnostic_test ,Data Collection ,Signal Processing, Computer-Assisted ,Acoustics ,Heart Rate, Fetal ,Computer Science Applications ,Noise ,Heart Sounds ,Heart sounds ,Female ,Algorithm ,Algorithms ,Software - Abstract
A valuable alternative to traditional diagnostic tools, such as ultrasonographic cardiotocography, to monitor general foetal well-being by means of foetal heart rate analysis is foetal phonocardiography, a passive and low cost recording of foetal heart sounds. In this paper, it is presented a simulator software of foetal phonocardiographic signals relative to different foetal states and recording conditions (for example different kinds and levels of noise). Before developing the software, a data collection pilot study was conducted with the purpose of specifically identifying the characteristics of the waveforms of the foetal and maternal heart sounds, since the available literature is not rigorous in this area. The developed software, due to the possibility to simulate different physiological and pathological foetal conditions and recording situations simply modifying some system parameters, can be useful as a teaching tool for demonstration to medical students and others and also for testing and assessment of foetal heart rate extraction algorithms from foetal phonocardiographic (fPCG) recordings. On this purpose, the simulator software was used to test an algorithm developed by the authors for foetal heart rate extraction considering different foetal heart rate parameters and signal to noise ratio values. Our tests demonstrated that simulated fPCG signals are very close to real fPCG recordings.
- Published
- 2012
33. Differential effect of atorvastatin and tacrolimus on proliferation of vascular smooth muscle and endothelial cells
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Arturo Giordano, Nicola Corcione, Paolo Ferraro, Simona Romano, Antonio Sorrentino, Anna Laura Di Pace, Mario Monaco, Michele Polimeno, Maria Fiammetta Romano, Giovanna Nappo, Giordano, A, Romano, Simona, Monaco, M, Sorrentino, A, Corcione, N, Di Pace, Al, Ferraro, P, Nappo, G, Polimeno, M, and Romano, MARIA FIAMMETTA
- Subjects
Male ,Time Factors ,Vascular smooth muscle ,Physiology ,medicine.medical_treatment ,Atorvastatin ,Pharmacology ,Muscle, Smooth, Vascular ,Myocyte ,Phosphorylation ,Receptor ,Cells, Cultured ,beta Catenin ,Aged, 80 and over ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,Endoglin ,Drug-Eluting Stents ,surgical procedures, operative ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,Cardiology and Cardiovascular Medicine ,medicine.drug ,DNA Replication ,proliferation ,Myocytes, Smooth Muscle ,Receptors, Cell Surface ,chemical and pharmacologic phenomena ,Cyclin B ,Tacrolimus ,Antigens, CD ,Physiology (medical) ,Human Umbilical Vein Endothelial Cells ,medicine ,Humans ,Pyrroles ,cardiovascular diseases ,Aged ,Cell Proliferation ,Dose-Response Relationship, Drug ,vascular cell ,business.industry ,Growth factor ,statin ,nutritional and metabolic diseases ,Cardiovascular Agents ,Heptanoic Acids ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business - Abstract
Although considered promising for use in drug-eluting stents (DES), tacrolimus failed clinically. Tacrolimus inhibits growth factor production but can also act as a growth factor on vascular smooth muscle cells (VSMC). This unexpected proliferative stimulus could reverse the beneficial effects of the drug on restenosis. We hypothesized that tacrolimus' association with statins, which lower cholesterol and impair cell proliferation, could restore tacrolimus' beneficial effect by abrogating the aberrant proliferative stimulus. Additionally, since maintenance of endothelial function represents a challenge for new-generation DES, we investigated the combined effect of tacrolimus and atorvastatin on endothelial cells. Human VSMC and umbilical vein endothelial cells (HUVEC) were incubated with 100 nM tacrolimus and increasing doses of atorvastatin (0–3.0 μM). Atorvastatin plus tacrolimus dose-dependently inhibited VSMC proliferation. The percentage of cells incorporating 5-bromo-2′-deoxyuridine (BrdU) in their DNA was 49 ± 14% under basal conditions, 62 ± 15% ( P = 0.01) with tacrolimus, 40 ± 22% with 3 μM atorvastatin, and 30 ± 7% ( P < 0.05) with 3 μM atorvastatin plus tacrolimus. Atorvastatin downregulated β-catenin, Erk1 and Erk2, and cyclin B in tacrolimus-stimulated VSMC. In contrast, atorvastatin plus tacrolimus did not affect proliferation of endothelial cells. The percentage of HUVEC incorporating BrdU in their DNA was 47 ± 8% under basal conditions, 58 ± 6% ( P = 0.01) with tacrolimus, 45 ± 4% with 3 μM atorvastatin, and 49 ± 1% with 3 μM atorvastatin plus tacrolimus. Both agents stimulated endoglin production by HUVEC. Taken together, these results suggest that, when combined with tacrolimus, atorvastatin exerts a dose-dependent antiproliferative effect on VSMC. In contrast, atorvastatin acts in concert with tacrolimus in HUVEC to stimulate production of endoglin, a factor that has an important role in endothelial repair. Our study supports the conclusion that prevention of postcoronary in-stent restenosis and late thrombosis may benefit of concomitant association of tacrolimus and high doses of atorvastatin.
- Published
- 2012
34. Sources of Variability in the Use of Standardized Perfusion Value for HCC Studies
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Michela D’Antò, Maria Romano, Paolo Bifulco, Mario Cesarelli, Francesco Fiore, D’Antò, M, Cesarelli, Mario, Fiore, F, Romano, Maria, and Bifulco, Paolo
- Subjects
medicine.medical_specialty ,business.industry ,Calibration (statistics) ,CT Perfusion ,Disease progression ,Value (computer science) ,Image processing ,Perfusion scanning ,Surgery ,Tumour tissue ,Calibration ,Medicine ,Radiology ,Liver Tumour ,business ,Perfusion ,Reliability (statistics) - Abstract
Hepatocellular carcinoma (HCC) is one of the world’s most common malignant tumours. As known, liver tumour tissue is characterised by an increased blood supply related to neoangionesis which causes an increased arterial vascularisation. CT Perfusion Imaging is an important, non invasive, technique for qualitative assessment of tissue perfusion after contrast agent administration. Nevertheless, being able to reliably quantifying angiogenesis is increasingly important to both the evaluation of the disease progression and monitoring of the therapeutic response of HCC. With this in mind, we believe that could be helpful to employ Standardised Perfusion Value (SPV), which has the potential to be a useful non-invasive marker of HCC angiogenesis. However, before using SPV in clinical practice, we need to verify its reliability. There are different causes of variability in applying the SPV index, e.g., the technical specifications of the CT system employed and the image processing system. In this paper the authors will analyse the variability of the BFa estimates and the variability due to the calibration procedure of the CT system, this with the objective of verifying how these factors affects SPV values. In our case, perfusion MDCT images of seventeen HCC patients were analysed. A software application, based on maximum slope method, was developed to compute BFa and SPV values. Four radiologists were involved in images processing evaluating variability related to ROI selection; each radiologist repeated the ROI drawing four times on the same image set. We computed the k calibration factor in order to evaluate SPV variability due to calibration protocol of CT systems. Results show that calibration factor variance, due to the position in the gantry, is less than BFa variability. So, we conclude that, when daily calibration is preferred, a simplified protocol, which neglects the dependence of K factor from the position, may be utilised; at least until the intrinsic variability of perfusion parameter computation operator-dependent will be reduced.
- Published
- 2012
35. Overexpression of gastrokine 1 in gastric cancer cells induces Fas-mediated apoptosis
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Paolo Arcari, Maurizio De Palma, Maria Romano, Emilia Rippa, Giovanna La Monica, Rosa Allocca, Rippa, Emilia, La Monica, G, Allocca, R, Romano, MARIA FIAMMETTA, De Palma, M, and Arcari, Paolo
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Fas Ligand Protein ,Physiology ,Peptide Hormones ,Clinical Biochemistry ,Apoptosis ,Biology ,medicine.disease_cause ,Fas ligand ,gastrokine ,Stomach Neoplasms ,Cell Line, Tumor ,Gastric mucosa ,medicine ,Humans ,Neoplastic transformation ,fas Receptor ,Enterochromaffin-like cell ,Caspase 3 ,gastric cancer ,Cell Biology ,Fas receptor ,apoptosi ,Cell biology ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Cancer cell ,Carcinogenesis ,Signal Transduction - Abstract
Gastrokine 1 (GKN1) is involved in the replenishment of the surface lumen epithelial cell layer, in maintaining the mucosal integrity, and could play a role in cell proliferation and differentiation. In fact, after injury of the gastric mucosa, restoration may occur very rapidly in the presence of GKN1. In contrast, if the protein is downregulated, the repair process may be hampered; however, application of GKN1 to gastrointestinal cells promoted epithelial restoration. Because GKN1 possesses some mitogenic effects on intestinal epithelial cells (IEC- 6) whereas this protein was also capable of inhibiting proliferation in gastric cancer cells (MKN28), we decided to study its involvement in apoptosis to understand the role of GKN1 in the modulation of inflammatory damage or tumorigenesis in gastric mucosa. We found by cytofluorimetry, Western blot and RT-PCR that the overexpression of GKN1 in gastric cancer cell lines (AGS and MKN28) stimulated the expression of Fas receptor. Moreover, compared to control cells, a significant increase of apoptosis, evaluated by TUNEL, was observed when GKN1 transfected cells were treated with a monoclonal antibody (IgM) anti-Fas. The activation of Fas expression was also observed by the overexpression of GKN1 in other cancer cell lines. Moreover, in GKN1-overexpressing gastric cancer cells exposed to FasL, the activation of caspase-3 was also observed by Western blot and fluorescence assays. Our data represent the first report for GKN1 as modulator of apoptotic signals and suggest that GKN1 might play an important role for tissue repair during the early stages of neoplastic transformation.
- Published
- 2011
36. FK506 Binding Proteins as Targets in Anticancer Therapy
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Simona Romano, Antonio Sorrentino, Maria Fiammetta Romano, Rita Bisogni, Anna Laura Di Pace, Luigi Sivero, Romano, Simona, Di Pace, A., Sorrentino, A., Bisogni, Rita, Sivero, Luigi, and Romano, MARIA FIAMMETTA
- Subjects
Cancer Research ,Tumor suppressor gene ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,Apoptosis ,Tacrolimus ,Tacrolimus Binding Proteins ,Neoplasms ,medicine ,Humans ,cancer ,Gene silencing ,PTEN ,PI3K/AKT/mTOR pathway ,Sirolimus ,Pharmacology ,biology ,targeted therapy ,medicine.disease ,FKBP ,Cell biology ,Calcineurin ,biology.protein ,Molecular Medicine ,Signal transduction ,Immunosuppressive Agents ,Signal Transduction - Abstract
FK506 binding proteins (FKBPs) are the intracellular ligands of FK506 and rapamycin, two natural compounds with powerful and clinically efficient immunosuppressive activity. In recent decades, a relevant role for immunosuppressants as anticancer agents has emerged. Especially, rapamycin and its derivatives are used, with successful results, across a variety of tumors. Of note, rapamycin and FK506 bind to FKBP12, and the resulting complexes interfere with distinct intracellular signaling pathways driven, respectively, by the mammalian target of rapamycin and calcineurin phosphatase. These pathways are related to T-cell activation and growth. Hyperactivation of the mammalian target of rapamycin (mTOR), particularly in cancers that have lost the tumor suppressor gene PTEN, plays an important pathogenetic role in tumor transformation and growth. The signaling pathway involving calcineurin and nuclear factors of activated T-lymphocytes is also involved in the pathogenesis of different cancer types and in tumor metastasis, providing a rationale for use of FK506 in anticancer therapy. Recent studies have focused on FKBPs in apoptosis regulation: Targeting of FKBP12 promotes apoptosis in chronic lymphocytic leukemia, FKBP38 knockdown sensitizes hepatoma cells to apoptosis, and FKBP51 silencing overcomes resistance to apoptosis in acute lymphoblastic leukemia, prostate cancer, melanoma, and glioma. Interestingly, derivatives of FK506 that have the same FKBP12-binding properties as FK506 but lack functional immunosuppressant activity, exert the same apoptotic effect as FK506 in chronic lymphocytic leukemia. These findings suggest that a direct FKBP inhibition represents a further mechanism of immunosuppressants anticancer activity. In this review, we focus on the role of FKBP members in apoptosis control and summarize the data on the antitumor effect of selective targeting of FKBP.
- Published
- 2010
37. Muscle motion and EMG activity in vibration treatment
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Antonio La Gatta, Paolo Bifulco, Antonio Fratini, Maria Romano, Mario Cesarelli, A., Fratini, A., La Gatta, Bifulco, Paolo, Romano, Maria, and Cesarelli, Mario
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Adult ,Male ,Acceleration ,Biomedical Engineering ,Biophysics ,Electromyography ,Vibration ,Displacement (vector) ,Motion ,03 medical and health sciences ,0302 clinical medicine ,Motion artifact ,medicine ,Humans ,Whole body vibration ,Computer Simulation ,Mechanical resonance ,Muscle, Skeletal ,Physics ,Artifact (error) ,medicine.diagnostic_test ,Muscles ,Resonance ,Equipment Design ,030229 sport sciences ,Anatomy ,Biomechanical Phenomena ,Muscle motion ,Stress, Mechanical ,Artifacts ,030217 neurology & neurosurgery ,Muscle Contraction ,Biomedical engineering - Abstract
The aim of this study is to highlight the relationship between muscle motion, generated by whole body vibration, and the correspondent electromyographic (EMG) activity and to suggest a new method to customize the stimulation frequency. Simultaneous recordings of EMG and tri-axial accelerations of quadriceps rectus femoris from fifteen subjects undergoing vibration treatments were collected. Vibrations were delivered via a sinusoidal oscillating platform at different frequencies (10-45 Hz). Muscle motion was estimated by processing the accelerometer data. Large EMG motion artifacts were removed using sharp notch filters centred at the vibration frequency and its superior harmonics. EMG-RMS values were computed and analyzed before and after artifact suppression to assess muscular activity. Muscles acceleration amplitude increased with frequency. Muscle displacements revealed a mechanical resonant-like behaviour of the muscle. Resonance frequencies and dumping factors depended on subject. Moreover, RMS of artifact-free EMG was found well correlated (R 2 = 0.82) to the actual muscle displacement, while the maximum of the EMG response was found related to the mechanical resonance frequency of muscle. Results showed that maximum muscular activity was found in correspondence to the mechanical resonance of the muscle itself. Assuming the hypothesis that muscle activation is proportional to muscle displacement, treatment optimization (i.e. to choose the best stimulation frequency) could be obtained by simply monitoring local acceleration (resonance), leading to a more effective muscle stimulation. Motion artifact produced an overestimation of muscle activity, therefore its removal was essential. © 2009 IPEM.
- Published
- 2009
38. FK506 can activate transforming growth factor- signalling in vascular smooth muscle cells and promote proliferation
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Nicola Corcione, Maria Romano, Maria Mallardo, Gaetano Calì, Paolo Ferraro, Arturo Giordano, Simona Romano, Anna D'Angelillo, Giordano, A., Romano, Simona, Mallardo, M., D'Angelillo, A., Calì, G., Corcione, N., Ferraro, P., and Romano, MARIA FIAMMETTA
- Subjects
DNA Replication ,medicine.medical_specialty ,TGF-beta signal ,Time Factors ,Vascular smooth muscle ,Physiology ,Activin Receptors ,medicine.medical_treatment ,FK506 ,Myocytes, Smooth Muscle ,Dioxoles ,Tacrolimus Binding Protein 1A ,Biology ,Collagen Type I ,Muscle, Smooth, Vascular ,Tacrolimus ,Transforming Growth Factor beta1 ,Cyclin D1 ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Protein Kinase Inhibitors ,Protein kinase B ,Cells, Cultured ,beta Catenin ,Cell Proliferation ,Dose-Response Relationship, Drug ,Cell growth ,TOR Serine-Threonine Kinases ,Growth factor ,Cardiovascular Agents ,Cell biology ,Blot ,Endocrinology ,Benzamides ,cardiovascular system ,vascular smooth muscle cell ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Protein Kinases ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Transforming growth factor - Abstract
Aims FK506-binding protein (FKBP) 12 is an inhibitor of transforming growth factor (TGF)-β type I receptors. Several lines of evidence support the view that TGF-β stimulates vascular smooth muscle cell (VSMC) proliferation and matrix accumulation. We investigated the effect of FK506, also known as tacrolimus, on cellular proliferation and on matrix protein production in human VSMCs. Methods and results We measured cell proliferation with flow cytometry using BrdU incorporation and fluorimetrically by measuring DNA concentration with Hoechst 33258. Western blot assay of whole-cell lysates was used to measure the levels of signalling proteins involved in proliferative pathways, in particular β-catenin, pErk, pAkt, pmTOR, and cyclin D1. Collagen synthesis was also investigated by Western blotting. The TGF-β signal was studied by both Western blotting and confocal microscopy. We used the SiRNA technique for FKBP12 gene silencing. Our results show that FK506 stimulates VSMC proliferation and collagen type I production. FK506 enhanced β-catenin levels and activated the extracellular signal-regulated kinase, Akt, and mammalian target of rapamycin kinase, which are important effectors of proliferation. Accordingly, cyclin D1 expression was increased. We also demonstrate that FK506 activates the TGF-β signal in VSMCs and that, through this mechanism, it stimulates cell proliferation. Conclusion FK506 can act as a growth factor for VSMCs.
- Published
- 2008
39. The effects of the vibratory stimulation of the neck muscles for the evaluation of stepping performance in Parkinson's Disease
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Fernanda Gallo, Bernardo Lanzillo, Paolo Bifulco, Maria Romano, Mario Cesarelli, Luigi Iuppariello, Giovanni D'Addio, F. Lullo, Iuppariello, Luigi, Bifulco, Paolo, D'Addio, Giovanni, Lanzillo, Bernardo, Lullo, Francesco, Gallo, Fernanda, Romano, Maria, and Cesarelli, Mario
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medicine.medical_specialty ,Parkinson's disease ,business.industry ,education ,Central nervous system ,Vibratory stimulation ,Delayed onset ,Biomedical Engineering ,Sensory system ,wireless accelerometer ,Computer Science Applications1707 Computer Vision and Pattern Recognition ,medicine.disease ,Neck muscles ,vibratory stimulation ,Vibratory stimulus ,medicine.anatomical_structure ,Physical medicine and rehabilitation ,mental disorders ,Medicine ,anticipatory postural adjustment ,business ,psychological phenomena and processes ,posture ,Balance (ability) - Abstract
The equilibrium system needs the coordination of three subsystems: sensory, skeletal and central nervous system. The central nervous system (CNS) counteracts equilibrium perturbations by means of compensatory and anticipatory postural adjustments (APA). While compensatory adjustments deal with actual perturbations of balance, the APA precede perturbations. The APA consist of preprogrammed activation of the muscles, according to task parameters [6] and are important to minimize the effects of planned postural perturbations. APA are specific to the movement, adapt to changes in external postural support by changing APA timing and magnitude. These APA are altered in Parkinson disease (PD) where have characterized by a reduced amplitude, an increased duration and a delayed onset of APA in tasks such as gait initiation. This study investigates the effects of a vibratory stimulus applied to the neck muscle groups in subjects with PD.
- Published
- 2015
40. Submovements composition and quality assessment of reaching movements in subjects with Parkinson's Disease
- Author
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Maria Romano, Giovanni D'Addio, Mario Cesarelli, Luigi Iuppariello, Paolo Bifulco, Iuppariello, Luigi, Bifulco, Paolo, Romano, Maria, Cesarelli, Mario, and D'Addio, Giovanni
- Subjects
noise ,Parkinson's disease ,Rehabilitation ,kinematic ,business.industry ,Movement (music) ,media_common.quotation_subject ,medicine.medical_treatment ,reaching movement ,Representation (systemics) ,Biomedical Engineering ,Computer Science Applications1707 Computer Vision and Pattern Recognition ,upper limb ,medicine.disease ,medicine ,Quality (business) ,Segmentation ,Artificial intelligence ,Functional ability ,Psychology ,business ,Composition (language) ,jerk ,Cognitive psychology ,media_common - Abstract
The segmentation of seemingly continuous movements into segments has been theorized for many years. These segments may be considered as “primitive” movements, or building blocks of more complex movements. The existence of these fragments, or sub-movements as they are called, has been supported by a wide range of studies over the past 100 years. Evidence for the existence of discrete sub-movements underlying continuous human movement has motivated many attempts to “extract” them. Recently, the sub-movement theory gained a great appeal in the rehabilitation field. In fact, understanding movement deficits following CNS lesions, and the relationships between these deficits and functional ability, is fundamental to the development of successful rehabilitation therapies. So, here a novel sub-movements decomposition method is proposed; it is based on a constrained-Expectation-Maximization. This representation allowed us to explore whether the movements are built up of elementary kinematic units by decomposing each signal into a weighted combination of 2D Gaussian functions. These can be used to assess the quality of reaching movements in subjects with Parkinson's Disease.
- Published
- 2015
41. A 9-independent-leads ECG system from 10 electrodes: A practice preserving WCT-less true unipolar ECG system
- Author
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Mario Cesarelli, Paolo Bifulco, Tara Julia Hamilton, Maria Romano, Gaetano D. Gargiulo, Elham Shabani Varaki, Gargiulo, Gaetano D., Varaki, Elham Shabani, Hamilton, Tara J., Bifulco, Paolo, Cesarelli, Mario, and Romano, Maria
- Subjects
medicine.diagnostic_test ,business.industry ,Computer science ,ECG ,Healthy subjects ,Pattern recognition ,12-lead ECG modification ,Information loss ,Wilson Central Terminal ,Electrode ,Recording electrode ,medicine ,Artificial intelligence ,Ecg signal ,business ,Electrode placement ,Electrocardiography ,Biomedical engineering - Abstract
Since the invention of the 12-lead Electrocardiography (ECG) it is taught that only eight out of the twelve signals recordable from the nine exploring electrodes are linearly independent. It is also accepted practice the use of other four linearly dependent signals to add diagnostic efficacy. Unfortunately, quality and usefulness of the 12-lead signals is directly correlated with electrode placement precision and concerns have been raised around intentional misplacements of limb electrodes also for resting ECG. In this paper we show that with a simple modification to the recording front-end, nine independent signals (one per recording electrode) can be recorded. These signals can be used to reconstruct precisely the 12-lead signals (without information loss) and a plethora of other linearly dependent new signals that can open an unexplored frontier in cardiac illnesses diagnosis. While we need to carefully evaluate the clinical implications of our findings, we present here the proposed circuit and a case study (healthy subject) showing the number of signals achievable and we quantify the effect upon the ECG signals of one of the most common intentional misplacement of electrodes.
- Published
- 2015
42. Immunomodulatory pathways regulate expression of a spliced FKBP51 isoform in lymphocytes of melanoma patients
- Author
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Simona Romano, Massimo Mascolo, Francesco Merolla, Massimiliano Scalvenzi, Maria Romano, Stefania Staibano, Anna D'Angelillo, Paolo A. Ascierto, Gennaro Ilardi, Paolo D'Arrigo, Ester Simeone, Egle Jovarauskaite, Romano, Simona, D'Angelillo, Anna, Staibano, Stefania, Ester, Simeone, Paolo, D'Arrigo, Paolo Antonio, Ascierto, Scalvenzi, Massimiliano, Mascolo, Massimo, Ilardi, Gennaro, Francesco, Merolla, Egle, Jovarauskaite, and Romano, MARIA FIAMMETTA
- Subjects
Male ,lymphocytes ,Cell ,B7-H1 Antigen ,Transforming Growth Factor beta ,Protein Isoforms ,Melanoma ,Aged, 80 and over ,Gene knockdown ,biology ,Author Keywords:melanoma ,Middle Aged ,CANCER ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,SAFETY ,Immunohistochemistry ,IMMUNE MODULATION ,Female ,Antibody ,Adult ,immune signature KeyWords Plus:T-CELL ,Adolescent ,PHASE ,FKBP51 spliced isoform ,Dermatology ,Peripheral blood mononuclear cell ,General Biochemistry, Genetics and Molecular Biology ,Tacrolimus Binding Proteins ,Young Adult ,Immune system ,Lymphocytes, Tumor-Infiltrating ,stomatognathic system ,PDL-1 ,ANTIBODY ,RECEPTOR ,medicine ,Humans ,Immunologic Factors ,Aged ,Cancer ,medicine.disease ,Alternative Splicing ,Immunology ,Cancer research ,biology.protein - Abstract
FKBP51 (gene FKBP5) is an immunophilin capable of immunosuppression expressed in melanoma and lymphocytes. We found increased levels of a spliced FKBP5 variant in the PBMCs of 124 patients with melanoma. This variant encodes for an unknown isoform (FKBP51s). We hypothesized that FKBP51s resulted from tumour interaction with immune cells, through PDL-1/PD-1. To address this issue, we performed melanoma/PBMC cocultures. Furthermore, the immunohistochemistry of 76 melanoma specimens served to investigate whether FKBP51s stained tumour infiltrating lymphocytes. Our results showed that PBMCs expressed FKBP51s when cocultured with melanoma. Tumour PDL-1 knockdown or anti-PD-1 reduced FKBP51s expression in cocultured PBMCs. IHC showed a strong FKBP51s signal in tumour infiltrating lymphocytes, and lymphocytes of the invasion front of the tumour, along with melanoma PDL-1 expression. When overexpressed in melanoma, FKBP51s facilitated PDL-1 expression on the cell surface. In conclusion, our study shows that FKBP51s marks the PBMCs of patients with melanoma and is exploited by the tumour to immunomodulate through PDL-1.
- Published
- 2015
43. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells
- Author
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Maria Romano, Vincenzo Poggi, Simona Romano, Annalisa Lamberti, Raffaella Avellino, Salvatore Venuta, Rita Bisogni, Rosanna Parasole, Avellino, R., Romano, S., Parasole, R., Bisogni, Rita, Lamberti, Annalisa, Poggi, V., and Romano, MARIA FIAMMETTA
- Subjects
Male ,Programmed cell death ,Adolescent ,Immunology ,Apoptosis ,Bone Marrow Cells ,acute lymphoblastic leukemia ,Protein Serine-Threonine Kinases ,Biology ,Biochemistry ,Tacrolimus Binding Proteins ,Wortmannin ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,Proto-Oncogene Proteins ,Acute lymphocytic leukemia ,Tumor Cells, Cultured ,medicine ,Humans ,Child ,Childhood Acute Lymphoblastic Leukemia ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Sirolimus ,rapamycin ,NF-kappa B ,Infant ,Drug Synergism ,Cell Biology ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,chemistry ,Doxorubicin ,Child, Preschool ,Cancer research ,Female ,Signal transduction ,Blast Crisis ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
The phosphatidyl-inositol 3 kinase (PI3k)/Akt pathway has been implicated in childhood acute lymphoblastic leukemia (ALL). Because rapamycin suppresses the oncogenic processes sustained by PI3k/Akt, we investigated whether rapamycin affects blast survival. We found that rapamycin induces apoptosis of blasts in 56% of the bone marrow samples analyzed. Using the PI3k inhibitor wortmannin, we show that the PI3k/Akt pathway is involved in blast survival. Moreover, rapamycin increased doxorubicin-induced apoptosis even in nonresponder samples. Anthracyclines activate nuclear factor κB (NF-κB), and disruption of this signaling pathway increases the efficacy of apoptogenic stimuli. Rapamycin inhibited doxorubicin-induced NF-κB in ALL samples. Using a short interfering (si) RNA approach, we demonstrate that FKBP51, a large immunophilin inhibited by rapamycin, is essential for drug-induced NF-κB activation in human leukemia. Furthermore, rapamycin did not increase doxorubicin-induced apoptosis when NF-κB was overexpressed. In conclusion, rapamycin targets 2 pathways that are crucial for cell survival and chemoresistance of malignant lymphoblasts—PI3k/Akt through the mammalian target of rapamycin and NF-κB through FKBP51—suggesting that the drug could be beneficial in the treatment of childhood ALL. (Blood. 2005;106:1400-1406)
- Published
- 2005
44. Evaluation of the monocyte counting by two automated haematology analysers compared with flow cytometry
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Ernesto Grimaldi, P. Carandente, M. F. Romano, M. De Caterina, R. Bisogni, F. Scopacasa, M. Pellegrino, Grimaldi, Ernesto, CARANDENTE GIARRUSSO, Patrizia, Scopacasa, FRANCESCO UMBERTO VITTOR, Romano, MARIA FIAMMETTA, Pellegrino, Maria, Bisogni, Rita, and DE CATERINA, Maurizio
- Subjects
Pathology ,medicine.medical_specialty ,Clinical Biochemistry ,Statistical difference ,Monocytes ,Mean difference ,Flow cytometry ,Automation ,Leukocyte Count ,Deming regression ,Monocyte count ,medicine ,Humans ,Blood Cells ,Hematologic Tests ,Chromatography ,medicine.diagnostic_test ,business.industry ,Monocyte ,Biochemistry (medical) ,Becton dickinson ,Reproducibility of Results ,Hematology ,General Medicine ,Flow Cytometry ,hematology analyser ,medicine.anatomical_structure ,count ,monocyte ,Tukey's range test ,business - Abstract
Summary The aim is to determine the monocyte count performance of the Bayer Diagnostics ADVIA®120 and Coulter® LH 750 automated haematology analysers and the results obtained by these two instruments were compared with those provided by Becton Dickinson FACScan flow cytometer using the combination of CD45/CD14 MoAb. Linearity and imprecision were also evaluated. The linearity of both instruments was good. Coulter® LH 750 showed better precision (4.3%) than ADVIA 120 (9.0%) both within and between batch. A significant correlation (r = 0.973) was found between the LH 750 and the flow cytometry method, while a modest one was observed between the latter and the ADVIA 120 (r = 0.880). When comparing the percentage of monocytes by means of one-way anova and Tukey test, it was found that the LH 750 provided the closest results in comparison with flow cytometry, with no statistical difference between the means (mean difference MO% = 0.6); however the difference was statistically different between the ADVIA 120 and flow cytometry (mean difference MO% = −4.06). These data were confirmed by Altman–Bland and Deming regression analyses.
- Published
- 2005
45. Nuclear Factor-κB Regulates Inflammatory Cell Apoptosis and Phagocytosis in Rat Carrageenin-Sponge Implant Model
- Author
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Maria Pia Cinelli, Maria Chiara Maiuri, Maria Teresa Ribecco, Gianfranco Tajana, Teresa Iuvone, Maria Caterina Turco, Rosa Carnuccio, Maria Romano, Daniela De Stefano, Guido Mele, Maiuri, MARIA CHIARA, Tajana, G., Iuvone, Teresa, De Stefano, D., Mele, G., Ribecco, M. T., Cinelli, Mariapia, Romano, MARIA FIAMMETTA, Turco, M. C., and Carnuccio, Rosa
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Male ,Time Factors ,Neutrophils ,Phagocytosis ,Blotting, Western ,Oligonucleotides ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Inflammation ,Carrageenan ,Pathology and Forensic Medicine ,Flow cytometry ,Transforming Growth Factor beta1 ,Cell Movement ,Transforming Growth Factor beta ,medicine ,Animals ,Rats, Wistar ,Transcription factor ,Nitrites ,Nitrates ,biology ,medicine.diagnostic_test ,NF-kappa B ,Transforming growth factor beta ,Flow Cytometry ,NFKB1 ,Immunohistochemistry ,Rats ,Cell biology ,Disease Models, Animal ,Immunology ,biology.protein ,Tumor necrosis factor alpha ,medicine.symptom ,Transcription Factors ,Regular Articles - Abstract
In the present study we investigated whether apoptosis and phagocytosis are regulated by nuclear factor (NF)-kB in a model of chronic inflammation. The subcutaneous implant of carrageenin-soaked sponges elicited an inflammatory response, characterized by a time-related increase of leukocyte infiltration into the sponge and tissue formation, which was inhibited by simultaneous injection of wild-type oligodeoxynucleotide decoy to NF-kB. Molecular and morphological analysis performed on infiltrated cells demonstrated: 1) an inhibition of NF-kB/DNA binding activity; 2) an increase of polymorphonuclear leukocyte apoptosis correlated either to an increase of p53 or Bax and decrease of Bcl-2 protein expression; and 3) an increase of phagocytosis of apoptotic polymorphonuclear leukocytes by macrophages associated with an increase of transforming growth factor-beta and decrease of tumor necrosis factor- alpha as well as nitrite/ nitrate production. Our results, showing that blockade of NF-kB by oligodeoxynucleotide decoy increases inflammatory cell apoptosis and phagocytosis, may contribute to lead to new insights into the mechanisms governing the inflammatory process. (Am J Pathol 2004, 165:115–126)
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- 2004
46. Pleiotropic roles in cancer biology for multifaceted proteins FKBPs
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Maria Romano, Anna D'Angelillo, Simona Romano, Romano, Simona, D'Angelillo, Anna, and Romano, MARIA FIAMMETTA
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Cell signaling ,Isomerase activity ,Protein Conformation ,Biophysics ,Computational biology ,Biology ,Bioinformatics ,medicine.disease_cause ,Biochemistry ,Neoplasm Protein ,Tacrolimus Binding Proteins ,Neoplasms ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Molecular Biology ,Cancer ,Tumorigenesi ,Animal ,Tacrolimus Binding Protein ,Peptidyl-prolyl-isomerase ,medicine.disease ,FK506 binding protein ,Neoplasm Proteins ,FKBP ,Tumor Markers, Biological ,Foldase ,Neoplasm ,Signal transduction ,Carcinogenesis ,Function (biology) ,Human ,Signal Transduction - Abstract
Background FK506 binding proteins (FKBP) are multifunctional proteins highly conserved across the species and abundantly expressed in the cell. In addition to a well-established role in immunosuppression, FKBPs modulate several signal transduction pathways in the cell, due to their isomerase activity and the capability to interact with other proteins, inducing changes in conformation and function of protein partners. Increasing literature data support the concept that FKBPs control cancer related pathways. Scope of the review The aim of the present article is to review current knowledge on FKBPs roles in regulation of key signaling pathways associated with cancer. Major conclusions Some family members appear to promote disease while others are protective against tumorigenesis. General significance FKBPs family proteins are expected to provide new biomarkers and small molecular targets, in the near future, increasing diagnostic and therapeutic opportunities in the cancer field. This article is part of a Special Issue entitled Proline-Directed Foldases: Cell Signaling Catalysts and Drug Targets.
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- 2014
47. Fractal behavior of heart rate variability during ECG stress test in cardiac patients
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Paolo Bifulco, Francesco Giallauria, Maria Romano, Giovanni D'Addio, Carlo Vigorito, Mario Cesarelli, Luigi Maresca, Elisa Fornasa, D'Addio, Giovanni, Romano, Maria, Maresca, L, Bifulco, Paolo, Fornasa, E, Giallauria, F, Cesarelli, Mario, Vigorito, Carlo, G. Nollo, G., D'Addio, M., Romano, L., Maresca, P., Bifulco, Fornasa, Elisa, F., Giallauria, M., Cesarelli, and C., Vigorito
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nonlinear analysi ,medicine.medical_specialty ,animal structures ,High intensity ,HRV ,Late recovery ,Chaotic systems, Electrocardiography, Finite difference method, Heart, Recovery ,Cardiac patients, Fractal analysis, Fractal behaviors, Heart rate variability, Higuchi's algorithms, Linear measures, Nonlinear measure, Typical propertie ,Fractal analysis ,Fractals ,Fractal ,Chaotic systems ,Stress test ,Internal medicine ,nonlinear analysis ,Cardiology ,medicine ,Ecg stress ,stress test ,Heart rate variability ,Psychology ,Simulation ,circulatory and respiratory physiology - Abstract
Linear measures of heart rate variability (HRV) during ECG stress test has been widely questioned due to the high signal non-stationary. Such limitations can be overcome by nonlinear measures of HRV based on typical properties of chaotic systems and deterministic fractal. Very few paper addressed such issue and aim of the paper is to describe fractal behavior of HRV during exercise. A fractal analysis by Higuchi's algorithm (FD) has been performed on 26 cardiac patients during resting, stress, early and late recovery phases of ECG stress test. Results showed a significant FD increasing values from resting to stress phase that was not recovered at all immediately after the exercise, and it was slightly recovered both during early and late recovery phase. The performance of fractal analysis of HRV during and after high intensity exercise suggests that it could be a useful index assessing relevant information about underlying physiological recovery. ?????? 2014 IEEE.
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- 2014
48. FKBP51 increases the tumour‐promoter potential of TGF‐beta
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Iris Scala, Paolo D'Arrigo, Adelaide Greco, Anna D'Angelillo, Massimiliano Scalvenzi, Maria Romano, Arturo Brunetti, Rita Bisogni, Simona Romano, Stefania Staibano, Romano, Simona, Anna, D'Angelillo, Paolo, D'Arrigo, Staibano, Stefania, Greco, Adelaide, Brunetti, Arturo, Scalvenzi, Massimiliano, Bisogni, Rita, Scala, Iri, and Romano, MARIA FIAMMETTA
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TGF-β ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Medicine (miscellaneous) ,Metastasis ,Gene expression ,TGF beta signaling pathway ,medicine ,Gene silencing ,Melanoma ,TGF‐β ,lcsh:R5-920 ,business.industry ,Research ,medicine.disease ,FKBP51 ,Cytokine ,Apoptosis ,Cell culture ,Cancer research ,Molecular Medicine ,lcsh:Medicine (General) ,business ,Transforming growth factor - Abstract
Background FKBP51 (FKBP5 Official Symbol) is a large molecular weight component of the family of FK506 binding proteins (FKBP). In recent years, research studies from our laboratory highlighted functions for FKBP51 in the control of apoptosis and melanoma progression. FKBP51 expression correlated with the invasiveness and aggressiveness of melanoma. Since a role for TGF‐β in the enhanced tumorigenic potential of melanoma cells is widely described, we hypothesized a cooperative effect between FKBP51 and TGF‐β in melanoma progression. Methods SAN and A375 melanoma cell lines were utilized for this study. Balb/c IL2γ NOD SCID served to assess the ability to colonize organs and metastasize of different cell lines, which was evaluated by in vivo imaging. Realtime PCR and western blot served for measurement of mRNA and protein expression, respectively. Results By comparing the metastatic potential of two melanoma cell lines, namely A375 and SAN, we confirmed that an increased capability to colonize murine organs was associated with increased levels of FKBP51. A375 melanoma cell line expressed FKBP51 mRNA levels 30‐fold higher in comparison to the SAN mRNA level and appeared more aggressive than SAN melanoma cell line in an experimental metastasis model. In addition, A375 expressed, more abundantly than SAN, the TGF‐β and the pro angiogenic TGF‐β receptor type III (TβRIII) factors. FKBP51 silencing produced a reduction of TGF‐β and TβRIII gene expression in A375 cell line, in accordance with previous studies. We found that the inducing effect of TGF‐β on Sparc and Vimentin expression was impaired in condition of FKBP51 depletion, suggesting that FKBP51 is an important cofactor in the TGF‐β signal. Such a hypothesis was supported by co immunoprecipitation assays, showing that FKBP51 interacted with either Smad2,3 and p300. In normal melanocytes, FKBP51 potentiated the effect of TGF‐β on N‐cadherin expression and conferred a mesenchymal‐like morphology to such round‐shaped cells. Conclusions Overall, our findings show that FKBP51 enhances some pro oncogenic functions of TGF‐β, suggesting that FKBP51‐overexpression may help melanoma to take advantage of the tumor promoting activities of the cytokine.
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- 2014
49. Expression of neuron-specific enolase in multiple myeloma and implications for clinical diagnosis and treatment
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Yongping Song, Haiping Yang, Xinghu Zhu, Ruihua Mi, Qian Wang, Xudong Wei, Qingsong Yin, Lin Chen, and Romano, Maria Fiammetta
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Enzymologic ,Male ,Pathology ,Lung Neoplasms ,medicine.medical_treatment ,Cancer Treatment ,lcsh:Medicine ,Pathology and Laboratory Medicine ,Gastroenterology ,Plasma Cell Disorders ,Lung and Intrathoracic Tumors ,Small Cell Lung Cancer ,80 and over ,Medicine and Health Sciences ,Medicine ,lcsh:Science ,Lung ,Multiple myeloma ,Cancer ,Aged, 80 and over ,Tumor ,Multidisciplinary ,medicine.diagnostic_test ,Lung Cancer ,Hematology ,Middle Aged ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Oncology ,Biomarker (medicine) ,Female ,Multiple Myeloma ,Immunohistochemical Analysis ,Research Article ,Adult ,medicine.medical_specialty ,endocrine system ,Clinical Pathology ,General Science & Technology ,Enolase ,Immunology ,Research and Analysis Methods ,Gene Expression Regulation, Enzymologic ,Rare Diseases ,Clinical Research ,Diagnostic Medicine ,Internal medicine ,Biopsy ,Biomarkers, Tumor ,Humans ,Lung cancer ,Immunoassays ,Immunohistochemistry Techniques ,Tumor marker ,Aged ,Neoplastic ,Chemotherapy ,business.industry ,Beta-2 microglobulin ,lcsh:R ,Biology and Life Sciences ,Cancers and Neoplasms ,medicine.disease ,Small Cell Lung Carcinoma ,Histochemistry and Cytochemistry Techniques ,Gene Expression Regulation ,nervous system ,Phosphopyruvate Hydratase ,Immunologic Techniques ,Clinical Immunology ,lcsh:Q ,business ,Biomarkers - Abstract
Objective To determine the expression of neuron-specific enolase (NSE) in patients with multiple myeloma (MM) and to evaluate its clinical value as a tumor marker and, an indicator of disease progression and treatment efficacy. Methods Using electrochemiluminescence immunoassay (ECLIA), we measured the serum levels of NSE in 47 healthy subjects (control group), 25 patients with small cell lung cancer (lung cancer group), and 52 patients with MM (MM group). For the MM group, serum NSE levels were measured and other disease indicators and related symptoms were monitored before and after chemotherapy. The relationship between NSE expression and other MM-related factors was analyzed. In addition, immunohistochemical staining was performed on bone marrow biopsy specimens from patients with MM. Results In the control group, serum NSE levels were within the normal range as previously reported, while the lung cancer group and the untreated MM group exhibited NSE levels that were significantly higher relative to the control group (P
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- 2014
50. Symbolic dynamic and frequency analysis in foetal monitoring
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Giovanni D'Addio, Maria Romano, Gianni Improta, Mario Cesarelli, Alfonso Maria Ponsiglione, Fabrizio Clemente, Romano, Maria, D'Addio, Giovanni, Clemente, F, Ponsiglione, A. M., Improta, Giovanni, and Cesarelli, Mario
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Engineering ,Frequency analysis ,medicine.medical_specialty ,medicine.diagnostic_test ,Remote patient monitoring ,business.industry ,Foetal heart rate variability ,Foetal monitoring ,Symbolic dynamics ,law.invention ,Fetal heart rate ,law ,Frequency domain ,Internal medicine ,medicine ,Cardiology ,Frequency domain analysis ,Heart rate variability ,Foetal development ,business ,Electrocardiography ,Biomedical engineering - Abstract
Foetal heart rate variability is widely considered an important parameter to assess foetal reactivity and wellbeing. Traditional approaches to analyze foetal heart rate and its variability, such as Time and Frequency Domain Analyses, have shown some limitations, due to their inability to highlight nonlinear dynamics potentially relevant. Hence, in the last decades, nonlinear analysis methods have gained a growing interest and the integration of parameters derived from these techniques and traditional ones could be a way to improve the assessment of foetal development and/or distress. In this work, we proposed a comparison between new index obtained with a nonlinear analysis (Symbolic Dynamic Analysis) and more traditional parameters computed by the power spectral density of the foetal heart variability signals (Frequency Domain Analysis). A dataset of 579 cardiotocographic signals from healthy foetuses, recorded from the 24th to the 42th gestation week, was examined using both above-mentioned methods. The obtained results demonstrate that Symbolic Dynamics, as much as Frequency Domain Analysis, could be a useful tool in foetal development assessing. �� 2014 IEEE.
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- 2014
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