44 results on '"Bruna Cerbelli"'
Search Results
2. The role of immune profile in predicting outcomes in cancer patients treated with immunotherapy
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Andrea Botticelli, Giulia Pomati, Alessio Cirillo, Simone Scagnoli, Simona Pisegna, Antonella Chiavassa, Ernesto Rossi, Giovanni Schinzari, Giampaolo Tortora, Francesca Romana Di Pietro, Bruna Cerbelli, Alessandra Di Filippo, Sasan Amirhassankhani, Alessandro Scala, Ilaria Grazia Zizzari, Enrico Cortesi, Silverio Tomao, Marianna Nuti, Silvia Mezi, and Paolo Marchetti
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Immunology ,chemokines ,lung neoplasms ,carcinoma ,prospective studies ,cytokines ,immune checkpoint inhibitors ,non-small-cell lung ,Carcinoma, Non-Small-Cell Lung ,tumor biomarker ,Immunology and Allergy ,immunotherapy ,humans ,soluble immune check-points ,carcinoma, non-small-cell lung - Abstract
BackgroundDespite the efficacy of immunotherapy, only a small percentage of patients achieves a long-term benefit in terms of overall survival. The aim of this study was to define an immune profile predicting the response to immune checkpoint inhibitors (ICIs).MethodsPatients with advanced solid tumors, who underwent ICI treatment were enrolled in this prospective study. Blood samples were collected at the baseline. Thirteen soluble immune checkpoints, 3 soluble adhesion molecules, 5 chemokines and 11 cytokines were analyzed. The results were associated with oncological outcomes.ResultsRegardless of tumor type, patients with values of sTIM3, IFNα, IFNγ, IL1β, IL1α, IL12p70, MIP1β, IL13, sCD28, sGITR, sPDL1, IL10 and TNFα below the median had longer overall survival (pConclusionThe combined evaluation of soluble molecules, rather than a single circulating factor, may be more suitable to represent the fitness of the immune system status in each patient and could allow to identify two different prognostic and predictive outcome profiles.
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- 2022
3. RNA-seq profiling reveals different pathways between remodeled vessels and myocardium in hypertrophic cardiomyopathy
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Annalinda Pisano, Loredana Le Pera, Raffaella Carletti, Bruna Cerbelli, Maria G. Pignataro, Angelina Pernazza, Fabrizio Ferre, Maria Lombardi, Davide Lazzeroni, Iacopo Olivotto, Ornella E. Rimoldi, Chiara Foglieni, Paolo G. Camici, and Giulia d'Amati
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coronary microvascular remodeling ,Physiology ,Myocardium ,remodeled arterioles dissected ,Myocardial Ischemia ,pathway enrichment analyses ,hypertrophic cardiomyopathy ,Cardiomyopathy, Hypertrophic ,Physiology (medical) ,Microvessels ,Humans ,RNA-Seq ,Cardiology and Cardiovascular Medicine ,Molecular Biology - Abstract
Coronary microvascular dysfunction (CMD) is a key pathophysiological feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and representing a critical determinant of patients' adverse outcome. The molecular mechanisms underlying the morphological and functional changes of CMD are still unknown. Aim of this study was to obtain insights on the molecular pathways associated with microvessel remodeling in HCM.Interventricular septum myectomies from patients with obstructive HCM (n = 20) and donors' hearts (CTRL, discarded for technical reasons, n = 7) were collected. Remodeled intramyocardial arterioles and cardiomyocytes were microdissected by laser capture and next-generation sequencing was used to delineate the transcriptome profile.We identified 720 exclusive differentially expressed genes (DEGs) in cardiomyocytes and 1315 exclusive DEGs in remodeled arterioles of HCM. Performing gene ontology and pathway enrichment analyses, we identified selectively altered pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls.We demonstrate the existence of distinctive pathways between remodeled arterioles and cardiomyocytes in HCM patients and controls at the transcriptome level.
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- 2022
4. Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus
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Elisabetta Botti, Roberta Pica, Alessia Butera, Carlo Chizzolini, Michel Gilliet, Raffaella Palazzo, Antonio Costanzo, K. Giannakakis, F. Stuber, Francesca Romana Spinelli, Valeria Riccieri, Laurence Feldmeyer, Luca Bianchi, Camilla Jandus, Francesca Spadaro, Eddie A. James, I. Daniels, Barbara Marinari, G. Valesini, L. G. Durrant, Fabrizio Conti, J. Di Lucca, Bruna Cerbelli, Cristiano Alessandri, Loredana Frasca, Roberto Lande, Pedro Romero, Monica Boirivant, Nicolas Gestermann, Mario Falchi, S. E. Auteri, S. Horstman, and Isabelle Surbeck
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0301 basic medicine ,Male ,T-Lymphocytes ,lcsh:Medicine ,Autoimmunity ,CXCR5 ,Anti-Citrullinated Protein Antibodies ,0302 clinical medicine ,Interferon ,antibodies ,Medicine ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,lcsh:Science ,antinuclear ,ddc:616 ,Multidisciplinary ,biology ,Phenotype ,Antibodies, Antinuclear ,Female ,Antibody ,medicine.drug ,Immunology ,Adaptive immunity ,Article ,anti-citrullinated protein antibodies ,antibodies, antinuclear ,antibody formation ,antimicrobial cationic peptides ,autoantibodies ,DNA ,dendritic cells ,female ,humans ,lupus erythematosus, systemic ,male ,psoriasis ,TH17 Cells ,03 medical and health sciences ,Settore MED/35 ,Cathelicidins ,Psoriasis ,Humans ,Secretion ,Autoantibodies ,030203 arthritis & rheumatology ,business.industry ,lcsh:R ,Autoantibody ,Dendritic Cells ,systemic ,medicine.disease ,In vitro ,030104 developmental biology ,Antibody Formation ,biology.protein ,Th17 Cells ,lcsh:Q ,business ,lupus erythematosus ,Antimicrobial Cationic Peptides - Abstract
LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.
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- 2020
5. 5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine
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Paolo Marchetti, Michela Roberto, Simone Scagnoli, Luana Lionetto, Bruna Cerbelli, Maurizio Simmaco, and A. Botticelli
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Adult ,Oncology ,medicine.medical_specialty ,Breast Neoplasms ,030226 pharmacology & pharmacy ,polymorphism ,Capecitabine ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Breast cancer ,5-FU degradation rate ,Internal medicine ,medicine ,capecitabine ,chemotherapy toxicity ,Humans ,Pharmacology (medical) ,Dihydrouracil Dehydrogenase (NADP) ,Methylenetetrahydrofolate Reductase (NADPH2) ,Aged ,Retrospective Studies ,Predictive biomarker ,Polymorphism, Genetic ,business.industry ,Thymidylate Synthase ,Middle Aged ,Prodrug ,medicine.disease ,Fluorouracil ,030220 oncology & carcinogenesis ,Toxicity ,Female ,business ,Biomarkers ,medicine.drug - Abstract
Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging. We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3–4 toxicities in breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II–IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3–4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1–37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values 2.10 ng/mL/106 cells/min) increased the risk of G3–4 adverse events (OR = 10.40 [95% IC: 1.48–7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate as a predictor of G3–4 toxicity occurrence (OR = 10.9 [95% IC 1.2–96.2], P = 0.03). The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity.
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- 2020
6. Radiologic-pathologic correlation in breast cancer: do MRI biomarkers correlate with pathologic features and molecular subtypes?
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Francesca Galati, Veronica Rizzo, Giuliana Moffa, Claudia Caramanico, Endi Kripa, Bruna Cerbelli, Giulia D’Amati, and Federica Pediconi
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Necrosis ,pathology (molecular) ,precision medicine ,biomarkers ,breast neoplasms ,multiparametric magnetic resonance imaging ,breast ,female ,humans ,magnetic resonance imaging ,necrosis ,retrospective studies ,Humans ,Radiology, Nuclear Medicine and imaging ,Breast Neoplasms ,Female ,Breast ,Magnetic Resonance Imaging ,Retrospective Studies - Abstract
Background Breast cancer (BC) includes different pathological and molecular subtypes. This study aimed to investigate whether multiparametric magnetic resonance imaging (mpMRI) could reliably predict the molecular status of BC, comparing mpMRI features with pathological and immunohistochemical results. Methods This retrospective study included 156 patients with an ultrasound-guided biopsy-proven BC, who underwent breast mpMRI (including diffusion-weighted imaging) on a 3-T scanner from 2017 to 2020. Histopathological analyses were performed on the surgical specimens. Kolmogorov–Smirnov Z, χ2, and univariate and multivariate logistic regression analyses were performed. Results Fifteen patients were affected with ductal carcinoma in situ, 122 by invasive carcinoma of no special type, and 19 with invasive lobular carcinoma. Out of a total of 141 invasive cancers, 45 were luminal A-like, 54 luminal B-like, 5 human epidermal growth factor receptor 2 (HER2) positive, and 37 triple negative. The regression analyses showed that size p = 0.025), while rim enhancement (p p = 0.001), peritumoural oedema (p p = 0.012) were negative predictors. Oppositely, round shape (p = 0.001), rim enhancement (p p p Conclusions mpMRI has been confirmed to be a valid noninvasive predictor of BC subtypes, especially luminal A and triple negative. Considering the central role of pathology in BC diagnosis and immunohistochemical profiling in the current precision medicine era, a detailed radiologic-pathologic correlation seems vital to properly evaluate BC.
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- 2021
7. Weekly chemotherapy as first line treatment in frail head and neck cancer patients in the immunotherapy era
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Francesco Vullo, Vincenzo Tombolini, Giulia d'Amati, Antonella Polimeni, Umberto Romeo, Marco Della Monaca, Sasan Amirhassankhani, Valentino Valentini, Marco de Vincentiis, Carlo Della Rocca, Carlo Catalano, Silverio Tomao, Paolo Sciattella, Bruna Cerbelli, Cira Di Gioia, Silvia Mezi, Fabio Ciurluini, Massimo Ralli, Alessio Cirillo, Francesca De Felice, Giulia Mammone, Paolo Marchetti, Giulia Pomati, Alessandro Corsi, and Andrea Botticelli
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Frail Elderly ,Alcohol abuse ,Cetuximab ,Pembrolizumab ,Docetaxel ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Frail patient population ,Medicine ,Humans ,Chemotherapy ,Head and neck cancer ,Aged ,Retrospective Studies ,Response rate (survey) ,business.industry ,Research ,General Medicine ,Immunotherapy ,medicine.disease ,cetuximab ,chemotherapy ,docetaxel ,first line ,frail patient population ,head and neck cancer ,First line ,030104 developmental biology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Objective First-line therapy for metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) has been revolutionized by the introduction of anti-checkpoint monoclonal antibodies, which have shown a significant improvement in overall survival (OS) gaining approval in a first line setting. Efficacy and safety of first-line weekly chemotherapy, compared to 3-weeks treatment, was retrospectively evaluated in a frail patient population with R/M HNSCC with the aim to evaluate its role as part of a personalized first-line approach. Methods A total of 124 patients with locally incurable R/M HNSCC receiving weekly (21) or three-weekly (103) chemotherapy plus cetuximab in a first line setting from December 2010 to September 2020 were retrospectively reviewed. Treatment outcomes in terms of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities were analysed. Results Patients in the three-week subgroup were ECOG PS 0 (39) and 1 (64) while patients in weekly group (21) were all PS 2. No significant differences were reported in terms of age, sex, smoking and previous alcohol abuse considering the two distinct subgroups. Moreover, no statistically significant difference was found in PFS and OS between the two treatment subgroups. The response rate was 35% (36 patients) and 34% (7 patients) in three-week and weekly treatment group, respectively. Seventy patients (68%) in the three-week group experienced chemotherapy-related toxicities, predominantly G3. In the weekly group a predominantly low-grade toxicity was found in a lower number of patients (52%). Conclusion The weekly schedule appears to be an active and safe strategy in frail patients with R/M HNSCC. Based on these data, a weekly schedule could be considered as a first line treatment in all frail patients excluded from pembrolizumab treatment and a study on the combination of weekly chemotherapy and immunotherapy should be performed.
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- 2021
8. 'Protenuria in SLE: Is it always lupus?'
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Vincenzo Leuzzi, Fabrizio Conti, Roberta Priori, Giulia d'Amati, Bruna Cerbelli, Rossana Scrivo, Cristiano Alessandri, Alessandra Ida Celia, and Francesca Diomedi-Camassei
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medicine.medical_specialty ,Biopsy ,030232 urology & nephrology ,Lupus nephritis ,fabry disease ,hydroxychloroquine ,proteinuria ,renal biopsy ,systemic lupus erythematosus ,Kidney ,Diagnosis, Differential ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Rheumatology ,immune system diseases ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Enzyme Replacement Therapy ,skin and connective tissue diseases ,030203 arthritis & rheumatology ,Proteinuria ,Systemic lupus erythematosus ,medicine.diagnostic_test ,urogenital system ,business.industry ,Remission Induction ,Hydroxychloroquine ,medicine.disease ,Dermatology ,Fabry disease ,Lupus Nephritis ,medicine.anatomical_structure ,Treatment Outcome ,Antirheumatic Agents ,Toxicity ,Fabry Disease ,Female ,Renal biopsy ,medicine.symptom ,business ,medicine.drug - Abstract
Proteinuria is one of the most typical manifestations of kidney involvement in Systemic Lupus Erythematosus (SLE). We report the case of a 23-year-old woman with a 6-year-long history of SLE presenting with proteinuria after a three-year remission on hydroxychloroquine. Kidney histological examination showed alterations inconsistent with lupus nephritis and suggestive of hydroxychloroquine toxicity or Fabry disease. The latter was confirmed by genetic assay.
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- 2021
9. The role of opioids in cancer response to immunotherapy
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Francesca Di Pietro, Federica De Galitiis, Enrico Cortesi, Giulia Mammone, Simone Scagnoli, Giulia Pomati, Michela Roberto, Silvia Mezi, Gaetano Lanzetta, Edoardo Cerbelli, Alessio Cirillo, Paolo Marchetti, Bruna Cerbelli, Alain Gelibter, Andrea Botticelli, and Maria Letizia Calandrella
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,early progression ,Lung Neoplasms ,medicine.medical_treatment ,lcsh:Medicine ,opioid receptors ,General Biochemistry, Genetics and Molecular Biology ,predictive factor ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,prognostic factor ,Retrospective Studies ,business.industry ,lcsh:R ,Cancer ,opioids ,Retrospective cohort study ,General Medicine ,Immunotherapy ,Drug interaction ,immunotherapy ,medicine.disease ,Primary tumor ,Analgesics, Opioid ,030104 developmental biology ,Opioid ,030220 oncology & carcinogenesis ,Concomitant ,business ,medicine.drug - Abstract
Background The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities. Methods This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. Results One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn’t (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37–2.09, p p Discussion Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well. Conclusions A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.
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- 2021
10. Maladaptive autophagy in the pathogenesis of autoimmune epithelitis in Sjögren's syndrome
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Angelica Gattamelata, Massimo Fusconi, Serena Colafrancesco, Bruna Cerbelli, B Monosi, Tania Colasanti, F. Giardina, Francesca Barone, Giulio Cavalli, Saba Nayar, Alessandra Ida Celia, Roberta Priori, Cristiana Barbati, S. De Vita, S. Gandolfo, Cesare Alessandri, Cesare Giordano, Roberto Giacomelli, Fabrizio Conti, S Scarpa, Onorina Berardicurti, E. Putro, Colafrancesco, Serena, Barbati, Cristiana, Priori, Roberta, Putro, Erisa, Giardina, Federico, Gattamelata, Angelica, Monosi, Benedetta, Colasanti, Tania, Celia, Alessandra Ida, Cerbelli, Bruna, Giordano, Carla, Scarpa, Susanna, Fusconi, Massimo, Cavalli, Giulio, Berardicurti, Onorina, Gandolfo, Saviana, Nayar, Saba, Barone, Francesca, Giacomelli, Roberto, De Vita, Salvatore, Alessandri, Cristiano, and Conti, Fabrizio
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autophagy ,sjögren's syndrome ,epithelium ,salivary gland epithelial cells (SGECs) ,Immunology ,Inflammation ,Pathogenesis ,stomatognathic system ,Rheumatology ,Annexin ,Sicca syndrome ,medicine ,Humans ,Immunology and Allergy ,Annexin A5 ,Caspase 3 ,business.industry ,Cell adhesion molecule ,Autophagy ,Germinal center ,stomatognathic diseases ,Sjogren's Syndrome ,Apoptosis ,Leukocytes, Mononuclear ,Cancer research ,medicine.symptom ,business ,Cell Adhesion Molecules ,Transcription Factors - Abstract
Objective: Salivary gland epithelial cells (SGECs) are key cellular drivers in the pathogenesis of primary Sjögren's syndrome (SS); however, the mechanisms sustaining SGEC activation in primary SS remain unclear. We undertook this study to determine the role of autophagy in the survival and activation of SGECs in primary SS. Methods: Primary SGECs isolated from the minor SGs of patients with primary SS or sicca syndrome were evaluated by flow cytometry, immunoblotting, and immunofluorescence to assess autophagy (autophagic flux, light chain 3 IIB [LC3-IIB], p62, LC3-IIB+/lysosome-associated membrane protein 1 [LAMP-1] staining), apoptosis (annexin V/propidium iodide [PI], caspase 3), and activation (intercellular adhesion molecule, vascular cell adhesion molecule). Focus score and germinal center presence were assessed in the SGs from the same patients to assess correlation with histologic severity. Human SG (HSG) cells were stimulated in vitro with peripheral blood mononuclear cells (PBMCs) and serum from primary SS patients in the presence or absence of autophagy inhibitors to determine changes in autophagy and epithelial cell activation. Results: SGECs from primary SS patients (n=24) exhibited increased autophagy (autophagic flux [P=0.001]; LC3-IIB [P=0.02]; p62 [P=0.064]; and as indicated by LC3-IIB/LAMP-1+ staining), increased expression of antiapoptotic molecules (Bcl-2 [P=0.006]), and reduced apoptosis (annexin V/PI [P=0.002]; caspase 3 [P=0.057]), compared to samples from patients with sicca syndrome (n=16). Autophagy correlated with histologic disease severity. In vitro experiments on HSG cells stimulated with serum and PBMCs from primary SS patients confirmed activation of autophagy and expression of adhesion molecules, which was reverted upon pharmacologic inhibition of autophagy. Conclusion: In primary SS SGECs, inflammation induces autophagy and prosurvival mechanisms, which promote SGEC activation and mirror histologic severity. These findings indicate that autophagy is a central contributor to the pathogenesis of primary SS and a new therapeutic target.
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- 2021
11. A multidisciplinary approach for the differential diagnosis between multiple primary lung adenocarcinomas and intrapulmonary metastases
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Francesca Belardinilli, Giulia d'Amati, Yasaman Mahdavian, Marco Anile, Angelina Pernazza, Maria Gemma Pignataro, Giuseppe Giannini, Bruna Cerbelli, Carlo Della Rocca, Anna Coppa, Federico Venuta, Massimiliano Bassi, and Angela Gradilone
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0301 basic medicine ,Male ,medicine.medical_specialty ,Lung Neoplasms ,Biopsy ,intrapulmonary metastasis ,Adenocarcinoma of Lung ,Tumor Staging ,Adenocarcinoma ,Pathology and Forensic Medicine ,Diagnosis, Differential ,Neoplasms, Multiple Primary ,03 medical and health sciences ,0302 clinical medicine ,Multidisciplinary approach ,Predictive Value of Tests ,metachronous ,Clinical information ,medicine ,Biomarkers, Tumor ,Humans ,Multiple tumors ,Pathological ,Aged ,Retrospective Studies ,Lung ,business.industry ,synchronous ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Cell Biology ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,multiple primary lung cancers ,NGS ,030220 oncology & carcinogenesis ,Female ,Radiology ,Differential diagnosis ,business ,Transcriptome - Abstract
Purpose The distinction between multiple primary lung cancers (MPLCs) and intrapulmonary metastases has a significant impact on tumor staging and therapeutic choices. Several criteria have been proposed to solve this diagnostic issue, but a definitive consensus is still missing. We tested the efficacy of a combined clinical, histopathological and molecular (“real world”) approach for the correct classification of multiple lung tumors in a selected cohort of patients. Methods 24 multiple lung tumors with a diagnosis of adenocarcinoma from 10 patients were retrospectively reviewed. Radiological, pathological and clinical information, including follow-up, were integrated with molecular profiling via a routine multigene panel sequencing. Results Comprehensive histologic assessment revealed readily distinguishable histologic patterns between multiple tumors suggesting unrelated lesions in 7 cases, in agreement with clinical, radiological and molecular data, thus leading to final diagnosis of MPLCs. In the remaining 3 cases, the differential diagnosis between MPLCs and intrapulmonary metastases was challenging, since the histologic features of the lesions were similar or identical. The final interpretation (2 MPLCs and 1 most likely intrapulmonary metastases) was reached thanks to the integration of all available data, and was confirmed by follow-up. Conclusions A multidisciplinary approach including a routinely affordable multigene panel sequencing is a useful tool to discriminate MPLCs from intrapulmonary metastases in multiple lung nodules sharing the adenocarcinoma histotype.
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- 2020
12. Induction chemotherapy in nonlaryngeal human papilloma virus-negative high-risk head and neck cancer: a real-world experience
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Michela Roberto, Francesco Vullo, Andrea Botticelli, Bruna Cerbelli, Paolo Marchetti, Marco de Vincentiis, Silvia Mezi, Antonella Polimeni, Giulia Pomati, Valentino Valentini, Vincenzo Tombolini, Alessandro Corsi, Alessio Cirillo, and Cira Di Gioia
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0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,oropharyngeal carcinoma ,oral cavity carcinoma ,cancer patients ,Docetaxel ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Carcinoma ,Humans ,Pharmacology (medical) ,Oral Cavity Carcinoma ,Radical surgery ,Stage (cooking) ,Laryngeal Neoplasms ,Aged ,Retrospective Studies ,Pharmacology ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,Head and neck cancer ,Papillomavirus Infections ,Cancer ,Induction chemotherapy ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,Progression-Free Survival ,030104 developmental biology ,Treatment Outcome ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Toxicity ,Female ,Fluorouracil ,Cisplatin ,business - Abstract
The role of induction chemotherapy in the multidisciplinary treatment of locally advanced, nonlaryngeal high-risk human papilloma virus (HPV)-negative head and neck squamous cells carcinoma (HNSCC) is uncertain in terms of overall survival (OS). The primary objective of this study was to identify possible predictive factors of survival and outcome in patients with HNSCC who were treated with induction chemotherapy. Fifty-nine patients with stage IVa/b HPV-negative non-laryngeal HNSCC (mostly originating from the oral cavity) who underwent induction chemotherapy at Policlinico Umberto I were reviewed. Treatment outcomes in term of objective response rate (ORR), progression-free survival (PFS), OS and toxicities were analyzed. A significant association between nodal status, ORR, ongoing smoking use, toxicities and OS was demonstrated. ORR (obtained in 61% of patients) was associated with a reduction in mortality of 80% (P< 0.0001). Early discontinuation after just one cycle of induction chemotherapy was associated to a significantly shorter OS. In oral cavity radical surgery with negative margins was obtained in 15/16 patients. In 42% of patients G3-G4 toxicity occurred. Toxicity requiring hospitalization occurred in 42% and 21% of patients with oropharyngeal and oral cavity carcinoma, respectively. Five patients died of treatment-related causes. No treatment-related mortality occurred in oral cavity patients. G5 toxicities were different according to the sub-sites of disease (P = 0.05). Induction chemotherapy in non-laryngeal high-risk HNSCC is an active strategy, most importantly in oral cavity cancer, even though burdened with a high (G ≥ 3) toxicity and early discontinuation rate. These data will however need to be confirmed in further and larger studies.
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- 2020
13. Mesenchymal cystic hamartoma presenting with pneumothorax: case report and review of the literature
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Federico Venuta, A Pernazza, Bruna Cerbelli, C. Della Rocca, Massimiliano Bassi, Martina Leopizzi, Giulia d'Amati, Maria Gemma Pignataro, and E Merenda
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Pulmonary and Respiratory Medicine ,Lung Diseases ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,diagnostic pitfalls ,Hamartoma ,030204 cardiovascular system & hematology ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Lung ,Aged ,business.industry ,Mesenchymal stem cell ,Pneumothorax ,lung ,mesenchymal cystic hamartoma ,pneumothorax ,General Medicine ,respiratory system ,medicine.disease ,Dermatology ,medicine.anatomical_structure ,030228 respiratory system ,Surgery ,Differential diagnosis ,Presentation (obstetrics) ,Cardiology and Cardiovascular Medicine ,business ,Rare disease - Abstract
Mesenchymal cystic hamartoma (MCH) of the lung is a rare disease, with an indolent course in the majority of cases. It can be single or multifocal and it is composed of primitive mesenchymal cells admixed with cystic spaces. Only few cases have been reported in the literature, with variable clinical presentation. We describe the case of a huge MCH, presenting with spontaneous pneumothorax in a 65-year-old man. Further, we provide a brief overview of the literature and discuss the differential diagnosis with other entities, and the possible diagnostic pitfalls.
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- 2020
14. Gut metabolomics profiling of non-small cell lung cancer (NSCLC) patients under immunotherapy treatment
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Bruna Cerbelli, Andrea Botticelli, Andrea Quagliariello, Federica Del Chierico, Alberta Tomassini, Pamela Vernocchi, Alfredo Miccheli, Federico Marini, Raffaele Giusti, Ilaria Grazia Zizzari, Marianna Nuti, Francesca Di Pietro, Sofia Reddel, Paolo Marchetti, Lorenza Putignani, and Ottavia Giampaoli
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0301 basic medicine ,Lung Neoplasms ,medicine.medical_treatment ,lcsh:Medicine ,non-small cell lung cancer (NSCLC) ,Gut flora ,NSCLC ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Metabolomics ,Cancer immunotherapy ,Carcinoma, Non-Small-Cell Lung ,Metabolome ,medicine ,Humans ,Progression-free survival ,biology ,business.industry ,Research ,lcsh:R ,General Medicine ,Immunotherapy ,immunotherapy ,gut metabolomics profiling ,medicine.disease ,biology.organism_classification ,Gastrointestinal Microbiome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Nivolumab ,business - Abstract
Background Despite the efficacy of immune checkpoint inhibitors (ICIs) only the 20–30% of treated patients present long term benefits. The metabolic changes occurring in the gut microbiota metabolome are herein proposed as a factor potentially influencing the response to immunotherapy. Methods The metabolomic profiling of gut microbiota was characterized in 11 patients affected by non-small cell lung cancer (NSCLC) treated with nivolumab in second-line treatment with anti-PD-1 nivolumab. The metabolomics analyses were performed by GC–MS/SPME and 1H-NMR in order to detect volatile and non-volatile metabolites. Metabolomic data were processed by statistical profiling and chemometric analyses. Results Four out of 11 patients (36%) presented early progression, while the remaining 7 out of 11 (64%) presented disease progression after 12 months. 2-Pentanone (ketone) and tridecane (alkane) were significantly associated with early progression, and on the contrary short chain fatty acids (SCFAs) (i.e., propionate, butyrate), lysine and nicotinic acid were significantly associated with long-term beneficial effects. Conclusions Our preliminary data suggest a significant role of gut microbiota metabolic pathways in affecting response to immunotherapy. The metabolic approach could be a promising strategy to contribute to the personalized management of cancer patients by the identification of microbiota-linked “indicators” of early progressor and long responder patients.
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- 2020
15. Publisher Correction: New insight into the mechanisms of ectopic fat deposition improvement after bariatric surgery
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Stefan R. Bornstein, Giulia Angelini, Giovanni Casella, Anna Severino, Nicola Basso, Melania Manco, Carla Giordano, Lidia Castagneto Gissey, Bruna Cerbelli, Alfredo Genco, Giulia Del Corpo, Geltrude Mingrone, Andreas L. Birkenfeld, University of Zurich, and Casella, Giovanni
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Male ,Materials science ,Primary Cell Culture ,10265 Clinic for Endocrinology and Diabetology ,lcsh:Medicine ,Bariatric Surgery ,610 Medicine & health ,Monocytes ,Perilipin-2 ,Non-alcoholic Fatty Liver Disease ,Risk Factors ,Autophagy ,Animals ,Humans ,Phosphorylation ,lcsh:Science ,Cells, Cultured ,1000 Multidisciplinary ,Multidisciplinary ,lcsh:R ,Adenylate Kinase ,Lipid Droplets ,Lipid Metabolism ,Publisher Correction ,Obesity, Morbid ,Rats ,Disease Models, Animal ,Treatment Outcome ,Diabetes Mellitus, Type 2 ,Liver ,Hepatocytes ,lcsh:Q ,Insulin Resistance ,Deposition (chemistry) ,Biomedical engineering - Abstract
Non-alcoholic fatty-liver disease (NAFLD) is frequent in obese patients and represents a major risk factor for the development of diabetes and its complications. Bariatric surgery reverses the hepatic features of NAFLD. However, its mechanism of action remains elusive. We performed a comprehensive analysis of the mechanism leading to the improvement of NAFLD and insulin resistance in both obese rodents and humans following sleeve-gastrectomy (SG). SG improved insulin sensitivity and reduced hepatic and monocyte fat accumulation. Importantly, fat accumulation in monocytes was well comparable to that in hepatocytes, suggesting that Plin2 levels in monocytes might be a non-invasive marker for the diagnosis of NAFLD. Both in vitro and in vivo studies demonstrated an effective metabolic regeneration of liver function and insulin sensitivity. Specifically, SG improved NAFLD significantly by enhancing AMP-activated protein kinase (AMPK) phosphorylation and chaperone-mediated autophagy (CMA) that translate into the removal of Plin2 coating lipid droplets. This led to an increase in lipolysis and specific amelioration of hepatic insulin resistance. Elucidating the mechanism of impaired liver metabolism in obese subjects will help to design new strategies for the prevention and treatment of NAFLD.
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- 2020
16. Autophagy occurs in lymphocytes infiltrating sjögren’s syndrome minor salivary glands and correlates with histological severity of salivary gland lesions
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Saba Nayar, Roberta Priori, Guido Valesini, Cristiana Barbati, Valentina Iannizzotto, Francesca Arienzo, Francesco Ciccia, Antonina Minniti, Elena Pipi, Raffaella Izzo, Bruna Cerbelli, Tania Colasanti, Fabrizio Conti, Cristiano Alessandri, Francesca Barone, Serena Colafrancesco, L. Mastromanno, Marta Vomero, Carla Giordano, Colafrancesco, S., Vomero, M., Iannizzotto, V., Minniti, A., Barbati, C., Arienzo, F., Mastromanno, L., Colasanti, T., Izzo, R., Nayar, S., Pipi, E., Cerbelli, B., Giordano, C., Ciccia, F., Conti, F., Valesini, G., Barone, F., Priori, R., and Alessandri, C.
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0301 basic medicine ,lymphocytes ,Pathology ,medicine.medical_specialty ,autophagy ,lcsh:Diseases of the musculoskeletal system ,Lymphocyte ,salivary glands ,ATG5 ,medicine.disease_cause ,Salivary Glands, Minor ,Flow cytometry ,Autoimmunity ,sjogren's syndrome ,03 medical and health sciences ,atg5 ,LC3B ,minor salivary gland ,sjögren’s syndrome ,germinal center ,humans ,salivary glands, minor ,0302 clinical medicine ,Downregulation and upregulation ,minor ,medicine ,030203 arthritis & rheumatology ,Salivary gland ,medicine.diagnostic_test ,business.industry ,Autophagy ,Germinal center ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:RC925-935 ,business ,Research Article - Abstract
Backgrounds The organization of minor salivary glands (MSG) infiltrates, in patients with Sjögren’s syndrome (SS), associates with disease severity and progression. Aberrant regulation of lymphocyte autophagy is involved in autoimmunity, and in previous work, we provided the first evidence of upregulated autophagy in CD4+ T cells infiltrating SS MSG. The aim of this study was to further explore autophagy in SS infiltrating and circulating lymphocytes and to investigate its role in disease histopathological progression. Methods After collection of 20 SS MSG, the presence of lymphocyte aggregates (foci) and the formation of germinal center (GC)-like structures were observed by H&E and confirmed by immunohistochemistry. The expression of autophagy-related genes, Atg5 and MAP1LC3A, was detected by RT-PCR on microdissected salivary gland tissue and control tonsils. In MSG and tonsils, autophagic lymphocytes were identified by the detection of the autophagosome protein LC3B visualized as LC3 puncta staining by immunofluorescence. Peripheral blood autophagy was assessed by flow cytometry in SS and healthy controls (HC). Results Real-time PCR demonstrated higher expression in the autophagy genes Atg5 and MAP1LC3A in MSG GCs as compared to both small foci (p = 0.0075, p = 0.0002) and GCs from tonsils (p = 0.0001, p = 0.0037). In MSG, LC3 puncta staining was detectable on both CD3+ and CD20+ lymphocytes; in tonsils, LC3 puncta was almost undetectable on all lymphocytes. Compared to HC (n = 20), flow cytometry did not reveal any increase of autophagy in SS circulating lymphocytes (n = 30). Conclusions In SS MSG, lymphocytes’ autophagy is a feature of infiltrating T and B cells and is associated with histological severity. Interestingly, in MSG aberrant regulation of autophagy is detectable in GC-like structures possibly indicating its involvement in the development and persistence of the autoimmune process within the lesions.
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- 2020
17. CD73 expression and pathologic response to neoadjuvant chemotherapy in triple negative breast cancer
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Maria Gemma Pignataro, Leopoldo Costarelli, Giulia d'Amati, Andrea Botticelli, Bruna Cerbelli, Paolo Marchetti, Annalinda Pisano, Domenico Campagna, Alessandro De Luca, Angelina Pernazza, Maria Pelullo, Paolo A. Ascierto, Lucio Fortunato, and Carlo Della Rocca
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Adult ,0301 basic medicine ,Oncology ,neoadjuvant treatment ,medicine.medical_specialty ,Stromal cell ,medicine.medical_treatment ,triple negative breast cancer ,pathologic response ,Triple Negative Breast Neoplasms ,chemical and pharmacologic phenomena ,Pathology and Forensic Medicine ,03 medical and health sciences ,Basal (phylogenetics) ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,Medicine ,5'-Nucleotidase ,Molecular Biology ,Triple-negative breast cancer ,Neoadjuvant therapy ,Aged ,Retrospective Studies ,Chemotherapy ,Univariate analysis ,business.industry ,Retrospective cohort study ,Cell Biology ,General Medicine ,Middle Aged ,Prognosis ,Neoadjuvant Therapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunohistochemistry ,Female ,business - Abstract
The immune system plays a key role in tumor surveillance and escape. Recently, CD73 has been proposed as a prognostic biomarker associated with disease-free survival and overall survival in triple negative breast cancer (TNBC). In this study, we investigated the role of both CD73 expression and stromal tumor–infiltrating lymphocytes (TILs) in predicting the pathologic response of TNBC to neoadjuvant chemotherapy (NACT). We retrospectively analyzed CD73 immunohistochemical expression and stromal TILs on 61 consecutive biopsies from patients who received standard NACT. Twenty-three patients (38%) achieved pathologic complete response (pCR). TILs were present in the majority of biopsies (93%) with percentages ranging from 2 to 80%. High TILs (≥ 50%) were found in 30% of cases, and in this group, pCR was achieved in 76.5% of cases. Levels of TILs were associated with a better pathologic response only at univariate analysis (p = 0.037). The median value of CD73 expression on tumor cells was 40%. In 32 (52.5%) basal biopsies, CD73 expression was below or equal to median value (“low CD73”). A pCR was obtained in 53% of cases with “low CD73” and in 21% with high CD73, and this was statistically different both at univariate (p = 0.011) and multivariate (p = 0.014) analysis. Our results suggest that CD73 expression better predicts the response to NACT than TILs in TNBC. Characterization of both TILs and microenvironment could be a promising approach to personalize treatment.
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- 2020
18. Exogenous peptides are able to penetrate human cell and mitochondrial membranes, stabilize mitochondrial tRNA structures, and rescue severe mitochondrial defects
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Maria Pelullo, Annalinda Pisano, Carla Giordano, Veronica Morea, Maria Gemma Pignataro, Gianni Colotti, Elena Perli, Ilaria Genovese, Giulia d'Amati, Valeria de Turris, Antonio Francesco Campese, Bruna Cerbelli, Anna Ghelli, Perli, Elena, Pisano, Annalinda, Pignataro, Maria Gemma, Campese, Antonio Francesco, Pelullo, Maria, Genovese, Ilaria, de Turris, Valeria, Ghelli, Anna Maria, Cerbelli, Bruna, Giordano, Carla, Colotti, Gianni, Morea, Veronica, and d'Amati, Giulia
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0301 basic medicine ,Mitochondrial Diseases ,Peptide ,rescuing peptides ,mitochondrial (mt) diseases ,mitochondrial targeting ,transfer RNA (tRNA) point mutations ,Biochemistry ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,RNA, Transfer ,Genetics ,Humans ,Point Mutation ,Amino Acids ,Molecular Biology ,Gene ,rescuing peptide ,chemistry.chemical_classification ,Chemistry ,Point mutation ,Nucleic acid sequence ,mitochondrial (mt) disease ,Transfection ,In vitro ,Cell biology ,Amino acid ,Mitochondria ,030104 developmental biology ,Transfer RNA ,Mitochondrial Membranes ,Peptides ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Mutations in mitochondrial transfer RNA (mt-tRNA) genes are responsible for a wide range of syndromes, for which no effective treatment is available. We previously reported that transfection of the nucleotide sequence encoding for the 16-residue β32_33 peptide from mitochondrial leucyl-tRNA synthetase ameliorates the cell phenotype caused by the mitochondrial tRNA mutations. In this work, we demonstrated that both the β32_33 peptide linked with the known (L)-Phe-(D)-Arg-(L)-Phe-(L)-Lys (FrFK) mitochondrial penetrating sequence and, strikingly, the β32_33 peptide per se, are able to penetrate both the plasma and mitochondrial membranes and exert the rescuing activity when exogenously administered to cells bearing the mutations m.3243A>G and m.8344A>G. These mutations are responsible for the most common and severe mt-tRNA-related diseases. In addition, we dissected the molecular determinants of constructs activity by showing that both the order of amino acids along the sequence and presence of positive charges are essential determinants of the peptide activity in cells and mt-tRNA structures stabilization in vitro. In view of future in vivo studies, this information may be required to design of β32_33 peptide-mimetic derivatives. The β32_33 and FrFK-β32_33 peptides are, therefore, promising molecules for the development of therapeutic agents against diseases caused by the mt-tRNA point mutations.
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- 2020
19. Tryptophan Catabolism as Immune Mechanism of Primary Resistance to Anti-PD-1
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Silvia Mezi, Simone Scagnoli, Alessio Cortellini, Andrea Botticelli, Bruna Cerbelli, Marianna Nuti, Ilaria Grazia Zizzari, Luana Lionetto, Maurizio Simmaco, Raffaele Giusti, Edoardo Cerbelli, Paolo Marchetti, Michela Roberto, and Giulia Pomati
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0301 basic medicine ,Male ,Programmed Cell Death 1 Receptor ,indoleamine-2 ,Gastroenterology ,Metastasis ,0302 clinical medicine ,Renal cell carcinoma ,Neoplasms ,Odds Ratio ,Medicine ,Immunology and Allergy ,Prospective cohort study ,Immune Checkpoint Inhibitors ,Original Research ,Aged, 80 and over ,education.field_of_study ,Hazard ratio ,Tryptophan ,indoleamine-2,3-dioxygenase ,anti-pd-1 ,kynurenine ,tryptophan metabolism ,tumor immunity ,Middle Aged ,Prognosis ,Primary tumor ,Treatment Outcome ,3-dioxygenase ,Female ,Nivolumab ,lcsh:Immunologic diseases. Allergy ,medicine.medical_specialty ,Population ,Immunology ,03 medical and health sciences ,Internal medicine ,Cell Line, Tumor ,Biomarkers, Tumor ,Humans ,education ,Aged ,Neoplasm Staging ,business.industry ,medicine.disease ,Head and neck squamous-cell carcinoma ,030104 developmental biology ,Drug Resistance, Neoplasm ,Neoplasm Grading ,business ,lcsh:RC581-607 ,030215 immunology - Abstract
Background: Clinical trials showed that only a subset of patients benefits from immunotherapy, suggesting the need to identify new predictive biomarker of resistance. Indoleamine-2,3-dioxygenase (IDO) has been proposed as a mechanism of resistance to anti-PD-1 treatment, and serum kynurenine/tryptophan (kyn/trp) ratio represents a possible marker of IDO activity.Methods: Metastatic non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and head and neck squamous cell carcinoma (HNSCC) treated with nivolumab as second-line treatment were included in this prospective study. Baseline serum kyn and trp levels were measured by high-performance liquid chromatography to define the kyn/trp ratio. The χ2-test and t-test were applied to compare frequencies and mean values of kyn/trp ratio between subgroups with distinct clinical/pathological features, respectively. Median baseline kyn/trp ratio was defined and used as cutoff in order to stratify the patients. The association between kyn/trp ratio, clinical/pathological characteristics, response, progression-free survival (PFS), and overall survival (OS) was analyzed.Results: Fifty-five patients were included. Mean baseline serum kyn/trp ratio was significantly lower in female than in male patients (0.048 vs. 0.059, respectively, p = 0.044) and in patients with lung metastasis than in others (0.053 vs. 0.080, respectively, p = 0.017). Mean baseline serum kyn/trp ratio was significantly higher in early progressor patients with both squamous and non-squamous NSCLC (p = 0.003) and with a squamous histology cancer (19 squamous NSCLC and 14 HNSCC, p = 0.029). The median value of kyn/trp ratio was 0.06 in the overall population. With the use of median value as cutoff, patients with kyn/trp ratio > 0.06 had a higher risk to develop an early progression (within 3 months) to nivolumab with a trend toward significance (p = 0.064 at multivariate analysis). Patients presenting a baseline kyn/trp ratio ≤0.06 showed a longer PFS [median 8 vs. 3 months; hazard ratio (HR): 0.49; 95% confidence interval (CI) 0.24–1.02; p = 0.058] and a significantly better OS than did those with a kyn/trp ratio > 0.06 (median 16 vs. 4 months; HR: 0.39; 95% CI 0.19–0.82; p = 0.013).Conclusion: Serum kyn/trp ratio could have both prognostic and predictive values in patients with solid tumor treated with immunotherapy, probably reflecting a primary immune-resistant mechanism regardless of the primary tumor histology. Its relative weight is significantly related to gender, site of metastasis, NSCLC, and squamous histology, although these suggestive data need to be confirmed in larger studies.
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- 2020
20. The 5-Ws of immunotherapy in head and neck cancer
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Mario Occhipinti, Silverio Tomao, Paolo Marchetti, Andrea Botticelli, Valerio M. Napoli, Sasan Amirhassankhani, Bruna Cerbelli, Grazia Sirgiovanni, Christiana Zorica Di Rocco, Federica Mazzuca, Silvia Mezi, Giulia Pomati, Alessandra Emiliani, and Marianna Nuti
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Immune checkpoint inhibitors ,medicine.medical_treatment ,Disease ,head and neck cancer ,immune checkpoint inhibitors ,immunosuppressive microenvironment ,immunotherapy ,PD-1/PD-L1 axis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,medicine ,Tumor Microenvironment ,Humans ,Immunologic Factors ,Tumor microenvironment ,business.industry ,Squamous Cell Carcinoma of Head and Neck ,Head and neck cancer ,Hematology ,Immunotherapy ,medicine.disease ,Clinical trial ,030104 developmental biology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,business - Abstract
The immune checkpoint inhibitors, a class of drugs able to block immune suppressive pathways in order to prime an anticancer immunity, revolutionized standard of care in platinum-refractory recurrent and/or metastatic head and neck carcinoma (R/M HNSCC). The PD-1/ PD-L1 axis is involved in the genesis, maintenance and progression of HNSCC and represents the target of checkpoint inhibitors. HNSCC is an immunosuppressive disease with a high inflammatory component in tumor microenvironment. Recent clinical trials showed that only a small subset of patients really benefits from immunotherapy. This review aims to highlight the five W-points of immunotherapy: why immunotherapy is promising in HNSCC, what is currently available in daily clinical practice, when immunotherapy can be integrated into the therapeutic strategy, where it can be useful according to predictive response biomarker, who, among patients, could get the best benefit from immunotherapy and how improve the achieved results.
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- 2020
21. Anti-aminoacyl-tRNA synthetase-related myositis and dermatomyositis: clues for differential diagnosis on muscle biopsy
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Marco Biffoni, Valeria Riccieri, Antonia De Luca, Maria Gemma Pignataro, Giulia d'Amati, Guido Valesini, Bruna Cerbelli, Silvia Berni, Roberta Priori, Annalinda Pisano, Carla Giordano, and Serena Colafrancesco
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Necrosis ,Adolescent ,dermatomyositis ,Biopsy ,anti-synthetase syndrome ,Autoimmune Diseases ,Pathology and Forensic Medicine ,Amino Acyl-tRNA Synthetases ,Diagnosis, Differential ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Myocyte ,Child ,Molecular Biology ,Myositis ,Aged ,Autoantibodies ,Aged, 80 and over ,030203 arthritis & rheumatology ,Autoimmune disease ,Muscle biopsy ,medicine.diagnostic_test ,business.industry ,Cell Biology ,General Medicine ,Middle Aged ,Dermatomyositis ,medicine.disease ,Female ,muscle biopsy ,medicine.symptom ,Differential diagnosis ,business ,myositis ,mtDNA damage ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Anti-synthetase syndrome is an autoimmune disease characterized by autoantibodies toward amino acyl-tRNA synthetases (ARS), anti-Jo 1 being the most commonly detected. Muscle damage develops in up to 90% of ARS-positive patients, characterized by a necrotizing myositis restricted to the perifascicular region. This topographic distribution of muscle damage may lead to a misdiagnosis of dermatomyositis (DM) at muscle biopsy. We compared morphological, immunohistochemical, and histoenzymatic features of muscle from ARS-positive patients (n = 11) with those of DM (n = 7) providing clues for their differential diagnosis. In addition, we evaluated markers of mitochondrial damage to provide a further distinction between these two entities. Necrosis occurred in the majority of ARS patients, mainly located in the perifascicular region. It was often limited to small foci of fibers, always associated with myocyte regeneration. This last often overwhelmed necrosis, representing occasionally the main finding. In DM, necrosis/regeneration was scarce while the peculiar feature was a diffuse atrophy of perifascicular fibers. These last showed decreased cytochrome c oxidase (COX) stain and mitochondrial DNA depletion, consistent with mitochondrial dysfunction. In contrast to DM, ARS displayed scattered COX-deficient fibers, not restricted to the perifascicular region. This feature occurred in up to 91% of patients, being prominent only in two.
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- 2017
22. A nomogram to predict 5-fluorouracil toxicity
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Luana Lionetto, Lidia Strigari, Concetta Elisa Onesti, Serena Macrini, Antonella Petremolo, Francesca Di Pietro, Giovanna Gentile, Andrea Botticelli, Elisabetta Anselmi, Michela Roberto, Maurizio Simmaco, Rosa Falcone, Bruna Cerbelli, Paolo Marchetti, Federica Mazzuca, Annalisa Milano, Marina Borro, and Mario Occhipinti
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Adult ,Male ,0301 basic medicine ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,gastrointestinal cancer ,Population ,Pharmacology ,Digestive System Neoplasms ,Gastroenterology ,nomogram ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Pharmacology (medical) ,Gastrointestinal cancer ,education ,Aged ,Retrospective Studies ,Aged, 80 and over ,education.field_of_study ,business.industry ,5-fluorouracil degradation rate ,toxicity ,Retrospective cohort study ,Middle Aged ,oncology ,pharmacology ,cancer research ,Nomogram ,medicine.disease ,Nomograms ,030104 developmental biology ,Oncology ,Pharmacogenetics ,030220 oncology & carcinogenesis ,Female ,DPYD ,Fluorouracil ,business - Abstract
Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27-87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3-4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.
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- 2017
23. Pharmacogenetic Approach to Toxicity in Breast Cancer Patients Treated with Taxanes
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Silvia Angelini, Valentina Sgroi, Francesca Di Pietro, Giovanna Gentile, Mario Occhipinti, Valentina Sini, Valeria Durante, Lidia Strigari, Andrea Botticelli, Paolo Marchetti, Raffaele Giusti, Patrizia Pellegrini, Alessandro Rossi, Concetta Elisa Onesti, Federica Mazzuca, Bruna Cerbelli, and Maurizio Simmaco
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Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,Genotype ,medicine.medical_treatment ,Antineoplastic Agents ,Breast Neoplasms ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,030226 pharmacology & pharmacy ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Breast cancer ,Internal medicine ,medicine ,Cytochrome P-450 CYP3A ,Humans ,abcb1 ,p-gp ,cytochrome p450 ,polymorphisms ,taxanes ,CYP3A5 ,Aged ,Aged, 80 and over ,Chemotherapy ,Taxane ,CYP3A4 ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Pharmacogenetics ,030220 oncology & carcinogenesis ,Toxicity ,Female ,Taxoids ,business - Abstract
BACKGROUND Taxanes are widely used to treat breast cancer patients. Taxanes are metabolized in human liver by the cytochrome CYP3A and are substrate of ATP-binding cassette multidrug transporters ABCB1. Single-nucleotide polymorphisms (SNPs) in genes involved in taxanes' metabolism could affect the inter-individual variability in reported toxicities. MATERIALS AND METHODS In this retrospective study, 152 women, affected by breast cancer and receiving a taxane-based chemotherapy, were enrolled. A peripheral blood sample was taken for genotyping the following polymorphisms: CYP3A4* 1B (A>G), CYP3A5 *3 (G>A) and ABCB1 (C1236T; C3435T). RESULTS We observed an association between ABCB1 3435 T/T and lower grade of toxicities (p=0.05). No other association were found for CYP 3A4 *1B, 3A5*3 and ABCB1 C1236T. CONCLUSION ABCB1 3435 T/T seems to be associated to lower rate of toxicity in patients receiving taxanes. Further prospective and larger studies should be performed to clarify the role of this polymorphism.
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- 2017
24. A Case Report of Subclinical Hypercortisolism Due to Adrenal Incidentaloma Complicated by Myasthenia Gravis after Adrenalectomy
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Cristiano Marinelli, Luigi Petramala, Antonio Concistrè, Federico Venuta, Bruna Cerbelli, Antonio Ciardi, Claudio Letizia, Anna Teresa Giallonardo, Giorgio De Toma, and Piernatale Lucia
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Cancer Research ,medicine.medical_specialty ,Thymoma ,Biopsy ,medicine.medical_treatment ,Adrenal Gland Neoplasm ,Adrenal Gland Neoplasms ,030209 endocrinology & metabolism ,Adrenocortical adenoma ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Myasthenia Gravis ,medicine ,Humans ,Subclinical infection ,medicine.diagnostic_test ,business.industry ,Adrenalectomy ,Mediastinum ,General Medicine ,Middle Aged ,medicine.disease ,Myasthenia gravis ,Treatment Outcome ,medicine.anatomical_structure ,Endocrinology ,Oncology ,030220 oncology & carcinogenesis ,Female ,Radiology ,Tomography, X-Ray Computed ,business ,Biomarkers ,Pyridostigmine Bromide - Abstract
A 62-year-old woman was admitted for evaluation of an incidentally discovered adrenal mass and hypertension. CT scan revealed a 7 cm mass in the right adrenal gland. After careful examination, the patient was diagnosed with subclinical hypercortisolism (SH). Adrenalectomy was performed. Histopathological examination showed an adrenocortical adenoma. Symptoms and signs of myasthenia gravis appeared 5 months later. CT of the chest showed a solid tissue mass in the mediastinum. The patient underwent a sternotomy with excision of the tumor, which histologically proved to be a type 2B thymoma. We describe a rare case of SH due to an incidentally discovered adrenocortical adenoma in a patient who manifested myasthenia gravis after surgical remission of the cortisol excess.
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- 2016
25. Esophageal carcinoma cuniculatum: systematic review of the literature and report of two cases
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Pasquale Berloco, Federico Francioni, Adriano Consolo, Tiziano De Giacomo, Giulia d'Amati, Quirino Lai, Bruna Cerbelli, Matteo Castrovillari, Fabio Melandro, and Angelina Pernazza
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0301 basic medicine ,squamous cell carcinoma ,Male ,medicine.medical_specialty ,Esophageal Neoplasms ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Esophagus ,Recurrence ,medicine ,Carcinoma ,Humans ,Basal cell ,Radical surgery ,Aged ,Verrucous carcinoma ,business.industry ,Total esophagectomy ,Cell Biology ,Middle Aged ,medicine.disease ,total esophagectomy ,verrucous carcinoma ,Esophagectomy ,Rare tumor ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Radiology ,Esophageal Squamous Cell Carcinoma ,Neoplasm Recurrence, Local ,business ,Systematic search - Abstract
Background and Aims Carcinoma cuniculatum (CC) is a rare variant of an extremely well-differentiated squamous cell carcinoma. The most commonly involved site is the skin, with a preference for the sole. Only 15 cases of esophageal CC have been reported so far. Based on published data, the clinical behavior of CC has not been clearly defined. We describe the clinical-pathologic features of two cases of esophageal CC, and provide a review of the available literature, to shed more light on this unusual tumor. Methods A detailed gross and histologic analysis was performed on two cases of surgically treated esophageal CC. The patients were followed-up after surgery. A systematic search was also done concerning studies focused on esophageal CC. A search of the electronic databases MEDLINE-PubMed was conducted using the following research terms: (esophagus) AND (cuniculatum carcinoma). Results Both patients were alive at last follow-up at six and nine months from surgery without any recurrence. Concerning the fifteen cases reported from the systematic review, median follow-up after surgery was very long as compared to common esophageal cancers (4.0 years), with only one recurrence observed. Conclusion CC shows an indolent clinical behavior, with a low recurrence rate after radical surgery. The diagnosis of this rare tumor is typically made after surgery. An aggressive approach is required with curative intents.
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- 2019
26. Predictive markers of long-term recurrence in chronic rhinosinusitis with nasal polyps
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Giulio Pagliuca, Salvatore Martellucci, Chiara Rosato, Carlo Della Rocca, Claudio Di Cristofano, Bruna Cerbelli, Davide Rosati, and Andrea Gallo
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Adult ,Male ,Reoperation ,Allergy ,medicine.medical_specialty ,Adolescent ,Lymphocyte Activation ,Gastroenterology ,eosinophilic infiltration ,IL-5 ,IL-8 ,lymphocytic infiltration ,nasal polyposis ,nasal polyps ,neutrophilic infiltration ,recurrence ,rhinosinusitis ,sinusitis ,03 medical and health sciences ,0302 clinical medicine ,Nasal Polyps ,Predictive Value of Tests ,Recurrence ,Internal medicine ,Statistical significance ,Eosinophilic ,Eosinophilia ,medicine ,Humans ,Nasal polyps ,Prospective Studies ,Sinusitis ,030223 otorhinolaryngology ,Prospective cohort study ,Asthma ,Aged ,Rhinitis ,business.industry ,Interleukin-8 ,Endoscopy ,Middle Aged ,medicine.disease ,Term (time) ,Phenotype ,Otorhinolaryngology ,Neutrophil Infiltration ,030220 oncology & carcinogenesis ,Chronic Disease ,Female ,Interleukin-5 ,business ,Biomarkers - Abstract
In last years, many attempts were made to recognize chronic rhinosinusitis with nasal polyps (CRSwNP) phenotypes focusing on identifying relevant key pathogenic molecules. Polyps recurrence rate ranges from 4% to 60%, so it's clear that not all clinical and immunologic factors associated with recurrence are known.We investigate the inflammatory profile in patients with long term recurrent and non-recurrent CRSwNPs and if a specific profile is associated with recurrence, comparing eosinophilic, neutrophilic and lymphocytic infiltration, as well as IL-5 and IL-8 expression to long term recurrence rate.This prospective study included 44 adult patients with CRSwNP treated with endoscopic sinus surgery between 2008 and 2010. Long term follow-up data (8-10 years) indicated that among 44 patients, 18 (40.1%) experienced long term recurrence of nasal polyposis needing maximal medical treatment or revision surgery. We realized two groups: one with patients who didn't present long term recurrence (26 patients) and another with patients who presented long term recurrence (18 patients) and in both groups eosinophilic, neutrophilic and lymphocytic infiltration and IL-5 and IL-8 expression were measured.The parameters that reached statistical significance (p 0.05) comparing the two groups were eosinophilic infiltration and IL-5 expression, whereas neutrophilic and lymphocytic infiltration, as IL-8 expression didn't show any significant difference. Asthma and aspirin intolerance seemed significantly more frequent in patients with recurrence, while allergy presented not statistically significant difference between two groups.We can conclude that high eosinophilic infiltration and high IL-5 expression in CRSwNP correlate with higher rate of long term recurrence, while neutrophilic and lymphocytic infiltration, and IL-8 expression don't correlate with it. These findings provide the opportunity to improve our ability to predict the prognosis of surgical intervention, although it is still needed to explore the optimal predictor of outcome in CRSwNP.
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- 2019
27. Kras/ADAM17-Dependent Jag1-ICD Reverse Signaling Sustains Colorectal Cancer Progression and Chemoresistance
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Carmine Nicoletti, Francesca Nardozza, Lucia Di Marcotullio, Sabrina Zema, Zein Mersini Besharat, Claudio Talora, Giulia d'Amati, Carlo Capalbo, Diana Bellavia, Giuseppe Giannini, Rocco Palermo, Bruna Cerbelli, Maria Pia Felli, Roberta Quaranta, Saula Checquolo, Isabella Screpanti, and Maria Pelullo
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,JAG1 ,Epithelial-Mesenchymal Transition ,Colorectal cancer ,Carcinogenesis ,Mutant ,Mice, Nude ,ADAM17 Protein ,medicine.disease_cause ,Pathogenesis ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Medicine ,Animals ,Humans ,business.industry ,Cancer ,medicine.disease ,HCT116 Cells ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Disease Progression ,Female ,KRAS ,Signal transduction ,Neoplasm Recurrence, Local ,business ,Colorectal Neoplasms ,HT29 Cells ,Jagged-1 Protein ,Signal Transduction - Abstract
Colorectal cancer is characterized by well-known genetic defects and approximately 50% of cases harbor oncogenic Ras mutations. Increased expression of Notch ligand Jagged1 occurs in several human malignancies, including colorectal cancer, and correlates with cancer progression, poor prognosis, and recurrence. Herein, we demonstrated that Jagged1 was constitutively processed in colorectal cancer tumors with mutant Kras, which ultimately triggered intrinsic reverse signaling via its nuclear-targeted intracellular domain Jag1-ICD. This process occurred when Kras/Erk/ADAM17 signaling was switched on, demonstrating that Jagged1 is a novel target of the Kras signaling pathway. Notably, Jag1-ICD promoted tumor growth and epithelial–mesenchymal transition, enhancing colorectal cancer progression and chemoresistance both in vitro and in vivo. These data highlight a novel role for Jagged1 in colorectal cancer tumor biology that may go beyond its effect on canonical Notch activation and suggest that Jag1-ICD may behave as an oncogenic driver that is able to sustain tumor pathogenesis and to confer chemoresistance through a noncanonical mechanism. Significance: These findings present a novel role of the transcriptionally active Jag1-ICD fragment to confer and mediate some of the activity of oncogenic KRAS.
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- 2019
28. NUT midline carcinoma: Current concepts and future perspectives of a novel tumour entity
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Luca Reggiani Bonetti, Carlo Messina, Andrea Botticelli, Valeria Merz, Massimiliano Salati, Cinzia Baldessari, and Bruna Cerbelli
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0301 basic medicine ,Oncogene Proteins, Fusion ,Disease ,Bioinformatics ,Translocation, Genetic ,Malignant transformation ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Therapeutic strategy ,NUT midline carcinoma ,BET inhibitors ,Diagnosis ,Epidemiology ,Nut midline carcinoma ,Treatment ,Cell Transformation, Neoplastic ,Carcinoma ,Nuclear Proteins ,business.industry ,Clinical course ,Cancer ,Hematology ,medicine.disease ,Clinical trial ,030104 developmental biology ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,business - Abstract
NMC is a recently recognized cancer type hallmarked by chromosomal translocation involving the NUT gene, a catastrophic event leading to fusion oncoprotein responsible for malignant transformation and tumor progression. The aggressiveness of disease together with a poor response to conventional treatment make NMC one of the most lethal cancer. Moreover, although until recently NMC has been poorly understood and largely neglected, the number of reported cases is steadily rising. Recently, in addition to its pathogenetic and diagnostic role, NUT-fusion oncoprotein has been shown to be amenable to targeted inhibition using BET inhibitors. Future clinical trials are warranted with the aim of investigate the incorporation of targeted agent into multimodal therapeutic strategy. Since new promising NUT-targeting drugs are emerging that may affect the clinical course, the correct and prompt recognition of NMC is key to improve patients' outcome.
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- 2019
29. Neuromuscular magnetic stimulation counteracts muscle decline in ALS patients: results of a randomized, double-blind, controlled study
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Maria Cristina Gori, Vittorio Frasca, Gabriella Dobrowolny, Antonio Musarò, Cristina Roseti, Carla Giordano, Elisa Lepore, Marco Ceccanti, C. Cambieri, Bruna Cerbelli, Emanuela Onesti, Maurizio Inghilleri, Annalinda Pisano, Eleonora Palma, Pierangelo Cifelli, and Gabriele Ruffolo
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0301 basic medicine ,Male ,muscle atrophy ,Magnetic Field Therapy ,Flexor carpi radialis muscle ,Adult ,Aged ,Amyotrophic Lateral Sclerosis ,Double-Blind Method ,Female ,Humans ,Middle Aged ,Muscles ,Muscular Atrophy ,Safety ,Muscle hypertrophy ,0302 clinical medicine ,Medicine ,Multidisciplinary ,medicine.diagnostic_test ,Muscle atrophy ,Compound muscle action potential ,medicine.anatomical_structure ,neuromuscular magnetic stimulation ,Anesthesia ,medicine.symptom ,Science ,Article ,ALS, muscle-nerve interplay ,NMJ ,gene expression ,03 medical and health sciences ,Atrophy ,Forearm ,Muscle biopsy ,business.industry ,ACh receptor ,medicine.disease ,ALS ,Neuromuscolar Magnetic Stimulation ,Median nerve ,030104 developmental biology ,muscle-nerve interplay ,business ,030217 neurology & neurosurgery - Abstract
The aim of the study was to verify whether neuromuscular magnetic stimulation (NMMS) improves muscle function in spinal-onset amyotrophic lateral sclerosis (ALS) patients. Twenty-two ALS patients were randomized in two groups to receive, daily for two weeks, NMMS in right or left arm (referred to as real-NMMS, rNMMS), and sham NMMS (sNMMS) in the opposite arm. All the patients underwent a median nerve conduction (compound muscle action potential, CMAP) study and a clinical examination that included a handgrip strength test and an evaluation of upper limb muscle strength by means of the Medical Research Council Muscle Scale (MRC). Muscle biopsy was then performed bilaterally on the flexor carpi radialis muscle to monitor morpho-functional parameters and molecular changes. Patients and physicians who performed examinations were blinded to the side of real intervention. The primary outcome was the change in the muscle strength in upper arms. The secondary outcomes were the change from baseline in the CMAP amplitudes, in the nicotinic ACh currents, in the expression levels of a selected panel of genes involved in muscle growth and atrophy, and in histomorphometric parameters of ALS muscle fibers. The Repeated Measures (RM) ANOVA with a Greenhouse-Geisser correction (sphericity not assumed) showed a significant effect [F(3, 63) = 5.907, p
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- 2019
30. CXCL13 as biomarker for histological involvement in Sjögren's syndrome
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Francesca Arienzo, Carla Giordano, Saba Nayar, Michele Bombardieri, Charlotte G Smith, Guido Valesini, Roberta Priori, Serena Colafrancesco, Davide Lucchesi, Joana Campos, Benjamin A Fisher, Antonina Minniti, Elena Pontarini, Valentina Iannizzotto, Massimo Fusconi, Francesca Barone, Elena Pipi, and Bruna Cerbelli
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lymphocytes ,0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Salivary Glands, Minor ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Internal medicine ,Biopsy ,medicine ,Humans ,Pharmacology (medical) ,CXCL13 ,Retrospective Studies ,030203 arthritis & rheumatology ,B-Lymphocytes ,Immunity, Cellular ,biomarkers ,cytokines and inflammatory mediators ,histopathology ,Sjögren's syndrome ,medicine.diagnostic_test ,Salivary gland ,business.industry ,Autoantibody ,Germinal center ,Middle Aged ,Prognosis ,Chemokine CXCL13 ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Sjogren's Syndrome ,Biomarker (medicine) ,Histopathology ,Female ,Sjogren s ,business ,Biomarkers ,Follow-Up Studies - Abstract
Objectives SS is an autoimmune condition characterized by systemic B-cell activation, autoantibody production and ectopic germinal centres’ formation within the salivary gland (SG). The extent of SG infiltrate has been proposed as a biomarker of disease severity. Plasma levels of CXCL13 correlate with germinal centres’ activity in animal models and disease severity in SS, suggesting its potential use as a surrogate serum marker to monitor local B-cell activation. The aim of this study was to evaluate the potential role of CXCL13 as a biomarker of SG pathology in two independent SS cohorts. Methods 109 patients with SS were recruited at Sapienza University of Rome (Italy) (n = 60), or at Queen Elizabeth Hospital in Birmingham and Barts Health NHS Trust in London (n = 49). Both sera and matched minor SG biopsy were available. Sicca (n = 57) and healthy subjects’ (n = 19) sera were used as control. Results CXCL13 serum level was higher in SS patients compared with controls. Correlations between its serum levels and a series of histomorphological parameters, including size of the aggregates and the presence germinal centres', were observed. Conclusion Our data foster the use of CXCL13 to monitor the extent of local pathology in SS and its validation in longitudinal clinical studies.
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- 2018
31. Synovial Hemangioma of the Temporomandibular Joint: Case Report
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Piero Cascone, Enrico Nastro-Siniscalchi, Valentino Vellone, Matteo Gualtieri, Bruna Cerbelli, and Giulio Bosco
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Male ,Pathology ,medicine.medical_specialty ,Soft Tissue Neoplasms ,Dentistry (miscellaneous)3502 Dental Assisting ,Synovial Hemangioma ,X ray computed ,Left temporomandibular joint ,Rare case ,medicine ,Humans ,Dentistry (miscellaneous) ,cardiovascular diseases ,Aged ,Temporomandibular Joint ,business.industry ,Synovial Membrane ,synovial hemangioma ,TMJ hemangioma ,TMJ neoplasm ,Temporomandibular Joint Disorders ,Magnetic Resonance Imaging ,eye diseases ,Temporomandibular joint ,body regions ,stomatognathic diseases ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Male patient ,sense organs ,Neurology (clinical) ,business ,Hemangioma ,Tomography, X-Ray Computed - Abstract
Hemangiomas are benign vasoformative neoplasms or developmental conditions of endothelial origin. Synovial hemangiomas arise from a synovial lined surface within a joint space. This report describes a case of synovial hemangioma of the left temporomandibular joint (TMJ) in a 65-year-old male patient. Histologic examination confirmed the diagnosis of synovial hemangioma. This is a rare case series, as the only case of synovial hemangioma with TMJ localization previously described was reported in 1988.
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- 2018
32. Can IDO activity predict primary resistance to anti-PD-1 treatment in NSCLC?
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Luana Lionetto, Annalinda Pisano, Marianna Nuti, Ilaria Grazia Zizzari, Maurizio Simmaco, Andrea Botticelli, Massimiliano Salati, Paolo Marchetti, Mazzuca Federica, and Bruna Cerbelli
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0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Lung Neoplasms ,Pleural effusion ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,lcsh:Medicine ,Kaplan-Meier Estimate ,General Biochemistry, Genetics and Molecular Biology ,IDO ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Progression-free survival ,Kynurenine ,Aged ,Performance status ,business.industry ,Research ,lcsh:R ,Tryptophan ,General Medicine ,Immunotherapy ,Quinolinic Acid ,medicine.disease ,Anti-PD-1 ,030104 developmental biology ,Nivolumab ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Multivariate Analysis ,Disease Progression ,Female ,business ,Quinolinic acid - Abstract
Background Immune checkpoint inhibitors have revolutionized the treatment paradigm of highly lethal malignancies like advanced non-small cell lung cancer (NSCLC), demonstrating long-term tumour control and extended patient survival. Unfortunately, only 25–30% of patients experience a durable benefit, while the vast majority demonstrate primary or acquired resistance. Recently, indoleamine 2,3-dioxygenase (IDO) activity has been proposed as a possible mechanism of resistance to anti-PD-1 treatment leading to an immunosuppressive microenvironment. Methods Pre-treatment serum concentrations of tryptophan (trp) and kynurenine (kyn) were measured by high-performance liquid chromatography tandem mass spectrometry in NSCLC patients treated with second-line nivolumab. The IDO activity was expressed with kyn/trp ratio. The associations between kyn/trp ratio and early progression, performance status (PS), age, sex, brain metastases, pleural effusion, progression free survival (PFS) and overall survival (OS) were analyzed using Spearman test and Mann–Whitney test. Results Twenty-six NSCLC patients were included in our study; 14 of them (54%) presented early progression (
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- 2018
33. Nivolumab in pretreated non-small cell lung cancer: continuing the immunolution
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Bruna Cerbelli, Cinzia Baldessari, Andrea Botticelli, and Massimiliano Salati
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,MEDLINE ,Antineoplastic Agents ,Docetaxel ,Kaplan-Meier Estimate ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Lung cancer ,business.industry ,Incidence (epidemiology) ,Antibodies, Monoclonal ,ORIGINAL REPORTS ,medicine.disease ,Survival Rate ,030104 developmental biology ,Editorial ,Nivolumab ,Treatment Outcome ,030220 oncology & carcinogenesis ,Taxoids ,Non small cell ,business - Abstract
Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non-small-cell lung cancer (NSCLC). We report updated results, including a pooled analysis of the two studies. Methods Patients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease progression during or after prior platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m
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- 2018
34. Breast cancer subtypes affect the nodal response after neoadjuvant chemotherapy in locally advanced breast cancer: Are we ready to endorse axillary conservation?
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Domenico Campagna, Federico Frusone, Annalinda Pisano, Massimo Monti, Andrea Botticelli, Lucio Fortunato, Leopoldo Costarelli, Bruna Cerbelli, Angelina Pernazza, Giulia d'Amati, Paola Scavina, and Ludovica De Vincentiis
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Oncology ,medicine.medical_specialty ,axillary surgery ,breast cancer ,lymph node surgery ,neoadjuvant chemotherapy ,pathologic complete response ,tumour subtype ,internal medicine ,surgery ,oncology ,Receptor, ErbB-2 ,medicine.medical_treatment ,Sentinel lymph node ,Locally advanced ,Breast Neoplasms ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Biopsy ,medicine ,Humans ,Stage (cooking) ,skin and connective tissue diseases ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Sentinel Lymph Node Biopsy ,Middle Aged ,medicine.disease ,Neoadjuvant Therapy ,Axilla ,medicine.anatomical_structure ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,NODAL ,business - Abstract
We evaluated the impact of breast cancer subtypes on pathologic complete response (pCR) in 181 patients with positive nodes undergoing neoadjuvant chemotherapy (NAC). After NAC, patients underwent surgery, with sentinel lymph node biopsy (SLNB) or axillary dissection (ALND). In 28.2% of cases a pCR was achieved, with the highest rate in Her2+ and triple negative tumors. Overall, nodal pCR was more frequent than breast pCR (P = 0.003) with higher percentages in Her2+ and LLB-Her2+ (P < 0.05). In the Her2+ group, nodal pCR was observed only with breast pCR. Thus, in Her2+ tumors, breast pCR predicts node pCR, supporting the use of SLNB in this subgroup to stage the axilla avoiding ALND.
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- 2018
35. Coronary atherosclerosis and sudden cardiac death in the young: another face of the culprit, another way of striking?
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Giulia d'Amati, Carla Giordano, and Bruna Cerbelli
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medicine.medical_specialty ,hypercholesterolemia ,business.industry ,coronary atherosclerosis ,connective tissue growth factor ,hydroxymethylglutaryl-coa reductase inhibitor ,sudden cardiac death (SCD) ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,medicine.disease ,Culprit ,Sudden cardiac death ,03 medical and health sciences ,0302 clinical medicine ,Death, Sudden, Cardiac ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Cardiology ,Humans ,Cardiology and Cardiovascular Medicine ,business ,Coronary atherosclerosis - Published
- 2018
36. PD-L1 Expression in TNBC: A Predictive Biomarker of Response to Neoadjuvant Chemotherapy?
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Andrea Botticelli, Massimo Monti, Domenico Campagna, Giulia d'Amati, Paolo Sciattella, Maria Mauri, Federica Mazzuca, Angelina Pernazza, Paolo Marchetti, Giuseppe Naso, Leopoldo Costarelli, Lucio Fortunato, and Bruna Cerbelli
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0301 basic medicine ,Oncology ,Adult ,medicine.medical_specialty ,Stromal cell ,Article Subject ,medicine.medical_treatment ,lcsh:Medicine ,Triple Negative Breast Neoplasms ,General Biochemistry, Genetics and Molecular Biology ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Pathological ,PD-L1 ,triple negative ,breast cancer ,Neoadjuvant therapy ,Triple-negative breast cancer ,Aged ,Chemotherapy ,Univariate analysis ,General Immunology and Microbiology ,business.industry ,lcsh:R ,General Medicine ,Middle Aged ,Neoadjuvant Therapy ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,business ,Research Article - Abstract
Triple negative breast cancer (TNBC) has an aggressive clinical behaviour, with a poorer prognosis compared to other subtypes. Recently, tumor-infiltrating lymphocytes (TILs) have been proposed as a predictive biomarker for a better clinical outcome and pathological response (pR) after neoadjuvant chemotherapy (NACT) in TNBC. These data confirm the role of the immune system in the neoplastic progression and in the response to therapy. We performed a retrospective analysis of 54 pre-NACT biopsies of TNBC and compared both the percentage of stromal TILs and the degree of PD-L1 expression with the extent of pR to standard NACT. A pathological complete response (pCR) was achieved in 35% of cases. Univariate analysis showed (i) a significant association between PD-L1 expression in ≥25% of neoplastic cells and the achievement of a pCR (p=0.024); (ii) a significantly higher frequency of pCR in cases showing ≥50% stromal TILs (p<0.001). However in the multivariate analysis only PD-L1 expression on tumor cells remained significantly associated with pCR (OR = 1,13; 95% CI 1,01–1,27), suggesting that the expression of this biomarker could be associated with a subpopulation of TNBC more likely to respond to chemotherapy. These data need to be confirmed by larger studies.
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- 2017
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37. Cardiac pathologic findings in 3 unusual cases of sudden cardiac death related to anorexiant drugs
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Bruna Cerbelli, Alberto Foà, Cira Di Gioia, Joaquín Lucena, Costantino Ciallella, Mariarosaria Aromatario, Ornella Leone, Valentina Agostini, Giulia d'Amati, Leone O., Agostini V., Foa A., Cerbelli B., di Gioia C.R.T., Aromatario M., Ciallella C., Lucena J., and d'Amati G.
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Adult ,Male ,medicine.medical_specialty ,Pathology ,Morpholine ,Morpholines ,Phenylpropanolamine ,Appetite Stimulants ,Autopsy ,030204 cardiovascular system & hematology ,Sudden death ,Anorexiant drug ,Cardiac sudden death ,Pathology and Forensic Medicine ,Sudden cardiac death ,Muscle hypertrophy ,03 medical and health sciences ,0302 clinical medicine ,Fatal Outcome ,Internal medicine ,medicine ,Humans ,Appetite Stimulant ,030212 general & internal medicine ,Adverse effect ,Bupropion ,business.industry ,Myocardium ,medicine.disease ,Cardiotoxicity ,Stenosis ,medicine.anatomical_structure ,Death, Sudden, Cardiac ,Ventricle ,Cardiology ,Anorexiant ,Female ,business ,Phendimetrazine ,Human - Abstract
Amphetamine congeners can be prescribed as anorexiant drugs despite their potential adverse effects, including cardiac toxicity. However, the morphologic features of cardiac damage related to protracted use of these compounds are unknown. We provide a detailed description of cardiac autopsy findings in 3 cases of sudden death associated with protracted use of high doses of phendimetrazine and/or phenylpropanolamine or bupropion prescribed as anorexiants, in association with other compounds. The main cardiac findings were similar in all 3 cases: (1) mild-moderate hypertrophy of the left ventricle and/or the septum; (2) myocardial nonischemic scarring (midmural and/or subepicardial) appearing as discrete foci or with a bandlike morphology; (3) mild-moderate intramural small vessel disease in the absence of significant epicardial coronary artery stenosis; and (4) acute/recent inflammatory lesions consistent with toxic myocarditis. In summary, the detailed pathology examination of the heart in these 3 cases revealed myocardial lesions identical to those reported in catecholamine myocardial damage in all their various stages of evolution. In the presence of a clinical history of long-term intake of anorexiants of this category, it is most important at autopsy to recognize and correctly interpret the acute and chronic myocardial lesions of the type herein described because they represent an anatomical substrate for arrhythmic death.
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- 2017
38. Pre-treatment assay of 5-fluorouracil degradation rate (5-FUDR) to improve prediction of 5-fluorouracil toxicity in gastro-esophageal cancer
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Federica Mazzuca, Adriana Romiti, Luana Lionetto, Giovanna Gentile, Andrea Botticelli, Elisa Concetta Onesti, Maurizio Simmaco, Bruna Cerbelli, Eva Mazzotti, Marina Borro, Paolo Marchetti, and Luca Marchetti
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0301 basic medicine ,Male ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,phenotypic test ,Drug-Related Side Effects and Adverse Reactions ,Esophageal Neoplasms ,Genotype ,5-FU degradation rate ,5-FU toxicity ,DPYD ,gastro-esophageal cancer ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Gastro ,Stomach Neoplasms ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,biology ,business.industry ,Cancer ,Esophageal cancer ,Middle Aged ,medicine.disease ,humanities ,Regimen ,030104 developmental biology ,Oncology ,Fluorouracil ,030220 oncology & carcinogenesis ,Methylenetetrahydrofolate reductase ,Toxicity ,biology.protein ,Female ,Clinical Research Paper ,business ,medicine.drug - Abstract
// Marina Borro 1,2 , Andrea Botticelli 3 , Federica Mazzuca 3 , Elisa Concetta Onesti 3 , Giovanna Gentile 1,2 , Adriana Romiti 3 , Bruna Cerbelli 4 , Eva Mazzotti 3 , Luca Marchetti 5 , Luana Lionetto 2 , Maurizio Simmaco 1,2 and Paolo Marchetti 2,3 1 Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), “Sapienza” University of Rome, Rome, Italy 2 Advanced Molecular Diagnostic, IDI-IRCCS, Rome, Italy 3 Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, Rome, Italy 4 Department of Radiological Oncological and Pathological Sciences, “Sapienza” University of Rome, Rome, Italy 5 Department of Clinical Oncology, “Sapienza” University of Rome, Rome, Italy Correspondence to: Andrea Botticelli, email: // Keywords : 5-FU degradation rate, phenotypic test, 5-FU toxicity, gastro-esophageal cancer, DPYD Received : August 16, 2016 Accepted : October 05, 2016 Published : October 11, 2016 Abstract Background: 5-fluorouracil (5-FU) based chemotherapy is the most common first line regimen used in gastric and gastroesophageal junction cancer , but development of severe toxicity is a main concern in the treatment. The present study is aimed to evaluate a novel pre-treatment assay, known as the 5-FU degradation rate (5-FUDR), as a predictive factor for 5-FU toxicity. Methods: Pre-treatment 5-FUDR and gene polymorphisms related to 5-FU metabolism ( DPYD IVS14+1G>A, MTHFR A1298T or C677T, TMYS TSER) were characterized in gastro-esophageal cancer patients. Association with toxicities was retrospectively evaluated, using multivariate logistic regression analysis. Results: 107 gastro-esophageal cancer patients were retrospectively analyzed. No relation between gene polymorphisms and toxicity were detected, while low ( 95 th centile) 5-FUDRs were associated with development of grade 3-4 toxicity (OR 11.14, 95% CI 1.09-113.77 and OR 9.63, 95% CI 1.70-54.55, p = 0.002). Conclusions: Compared to currently used genetic tests, the pre-treatment 5-FUDR seems useful in identifying patients at risk of developing toxicity.
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- 2016
39. Potential role for the VDR agonist elocalcitol in metabolic control: Evidences in human skeletal muscle cells
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Clara Crescioli, Luigi Di Luigi, Bruna Cerbelli, Guido Valesini, Salvatore Minisola, Gabriella B. Vannelli, Silvia Migliaccio, Katia Stefanantoni, Andrea Lenzi, Annalinda Pisano, Clarissa Corinaldesi, Cristina Antinozzi, Valeria Riccieri, and Carla Giordano
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0301 basic medicine ,Male ,inflammatory myopathy ,Endocrinology, Diabetes and Metabolism ,Muscle Fibers, Skeletal ,Calcitriol receptor ,human skeletal muscle cells ,metabolism ,VDR agonist ,endocrinology, diabetes and metabolism ,medicine (all) ,biochemistry ,molecular medicine ,molecular biology ,endocrinology ,clinical biochemistry ,cell biology ,0302 clinical medicine ,Homeostasis ,Insulin ,Resistin ,Vitamin D ,diabetes and metabolism ,Aged, 80 and over ,Middle Aged ,Lipids ,medicine.anatomical_structure ,Female ,Adult ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Biology ,vitamin D deficiency ,03 medical and health sciences ,Young Adult ,Calcitriol ,Internal medicine ,Myokine ,medicine ,Vitamin D and neurology ,Humans ,Muscle, Skeletal ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Aged ,Inflammation ,Interleukin-6 ,Gene Expression Profiling ,Skeletal muscle ,medicine.disease ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Microscopy, Fluorescence ,Receptors, Calcitriol - Abstract
Vitamin D plays a pivotal role to maintain skeletal muscle integrity and health. Vitamin D deficiency characterizes inflammatory myopathy (IM) and diabetes, often overlapping diseases involving skeletal muscle damage. Vitamin D receptor (VDR) agonists likely exert beneficial effects in both IM and metabolic disturbances. We aim to evaluate in vitro the effect of elocalcitol, a non-hypercalcemic VDR agonist, on the biomolecular metabolic machinery of human skeletal muscle cells (Hfsmc), vs. insulin (I). We analyzed GLUT4, Flotillin-1, Caveolin-3 and Caveolin-1 cell expression/localization; mTOR, AKT, ERK and 4E-BP1 phosphorylation; IL-6 myokine release; VDR expression. We investigated in vivo vitamin D status in IM subjects, evaluating VDR muscular expression and serum vitamin D with metabolism-related parameters, as glycemia, triglycerides, cholesterol, resistin and adiponectin. In Hfsmc, elocalcitol exerted an I-like effect, promoting GLUT4 re-localization in Flotillin-1, Caveolin-3 and Caveolin-1 positive sites and mTOR, AKT, ERK, 4E-BP1 activation; it enhanced IL-6 myokine release. IM subjects, all normoglycemic, showed VDR/vitamin D deficiency that, together with high lipidemic and resistin profile, possibly increases the risk to develop metabolic diseases. VDR agonists as elocalcitol may be therapeutic tools for skeletal muscle integrity/function maintenance, an indispensable condition for health homeostasis.
- Published
- 2016
40. Nonischemic left ventricular scar and cardiac sudden death in the young
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Vincenzo Palmieri, Enrico De Dominicis, Carla Giordano, Bruna Cerbelli, Barbara Poscolieri, Cira Di Gioia, Elena Perli, C. Ciallella, Giulia d'Amati, Paolo Zeppilli, and Annalinda Pisano
- Subjects
Male ,Biopsy ,DNA Mutational Analysis ,Autopsy ,030204 cardiovascular system & hematology ,Sudden cardiac death ,Coronary artery disease ,cardiac sudden death ,Electrocardiography ,0302 clinical medicine ,Risk Factors ,LDAC ,Prevalence ,030212 general & internal medicine ,Child ,ARVC/D ,Settore M-EDF/01 - METODI E DIDATTICHE DELLE ATTIVITÀ MOTORIE ,medicine.anatomical_structure ,Phenotype ,Italy ,Molecular Diagnostic Techniques ,Child, Preschool ,cardiovascular system ,Cardiology ,Female ,Cardiomyopathies ,Adult ,Genetic Markers ,medicine.medical_specialty ,Myocarditis ,Adolescent ,Sudden death ,Right ventricular cardiomyopathy ,Pathology and Forensic Medicine ,Diagnosis, Differential ,03 medical and health sciences ,QRS complex ,Cicatrix ,Young Adult ,Age Distribution ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,nonischemic left ventricular scar ,Genetic Predisposition to Disease ,cardiovascular diseases ,business.industry ,Myocardium ,Infant ,medicine.disease ,Coronary arteries ,myocarditis ,Death, Sudden, Cardiac ,Mutation ,business - Abstract
Nonischemic left ventricular scar (NLVS) is a pattern of myocardial injury characterized by midventricular and/or subepicardial gadolinium hyperenhancement at cardiac magnetic resonance, in absence of significant coronary artery disease. We aimed to evaluate the prevalence of NLVS in juvenile sudden cardiac death and to ascertain its etiology at autopsy. We examined 281 consecutive cases of sudden death of subjects aged 1 to 35 years. NLVS was defined as a thin, gray rim of subepicardial and/or midmyocardial scar in the left ventricular free wall and/or the septum, in absence of significant stenosis of coronary arteries. NLVS was the most frequent finding (25%) in sudden deaths occurring during sports. Myocardial scar was localized most frequently within the left ventricular posterior wall and affected the subepicardial myocardium, often extending to the midventricular layer. On histology, it consisted of fibrous or fibroadipose tissue. Right ventricular involvement was always present. Patchy lymphocytic infiltrates were frequent. Genetic and molecular analyses clarified the etiology of NLVS in a subset of cases. Electrocardiographic (ECG) recordings were available in more than half of subjects. The most frequent abnormality was the presence of low QRS voltages (
- Published
- 2016
41. A novel LAMP2 mutation associated with severe cardiac hypertrophy and microvascular remodeling in a female with Danon disease: a case report and literature review
- Author
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Adele D'Amico, Daniela D'Angelantonio, Diana Giannarelli, Giulia d'Amati, Silvia Majore, Martina Lipari, Enrico Bertini, Bruna Cerbelli, Carmelilia De Bernardo, Francesco Musumeci, Laura Masuelli, Federica Re, Taisia Polidori, Carla Giordano, Irene Bottillo, Andrea Avella, Paola Grammatico, and Elisabetta Zachara
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pathology ,Cardiac hypertrophy ,Danon disease ,Genotype–Phenotype correlations ,LAMP2 ,Lysosomal vacuoles ,Microvascular remodeling ,X-chromosome inactivation study (XCI) ,medicine.medical_treatment ,Cardiomyopathy ,Cardiomegaly ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Lysosomal-Associated Membrane Protein 2 ,medicine ,Humans ,Genetic Association Studies ,Ejection fraction ,business.industry ,Hypertrophic cardiomyopathy ,General Medicine ,medicine.disease ,Glycogen Storage Disease Type IIb ,030104 developmental biology ,medicine.anatomical_structure ,Ventricle ,Heart failure ,Ventricular assist device ,Mutation ,Cardiology ,Female ,Wolff-Parkinson-White Syndrome ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery - Abstract
Background Danon disease (DD) is a rare disorder characterized by cardiomyopathy, intellectual disability, and proximal myopathy. It is caused by mutations in the LAMP2 gene on X chromosome. Female patients most often present with late-onset cardiomyopathy and slow disease progression, but early-onset cases with unfavorable prognosis have been reported. Case report We describe the clinical, pathological, and molecular features of a novel LAMP2 c.453delT mutation in a female patient with severe hypertrophic cardiomyopathy, Wolff Parkinson White (WPW) syndrome and rapid progression to heart failure, requiring heart transplant. Immunohistochemical analysis of LAMP2 in the explanted heart revealed a mosaic pattern of distribution, with discrete clusters of either stained or unstained cardiac myocytes, the latter being more frequent in the septum. These findings paralleled X chromosome inactivation within the myocardium. Interestingly, multiple foci of microscarring were found on histology in the Left Ventricle (LV) free wall and septum, in a close spatial relationship with remodeling and severe stenosis of intramural coronary arterioles. Conclusions Our findings suggest that several features may contribute to the early and severe cardiac phenotype in female DD patients. The type of mutation may account for the early disease onset, while both the inhomogeneous distribution of LAMP2 loss and the presence of microvascular remodeling may be determinant in the rapid progression to heart failure.
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- 2016
42. New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study
- Author
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Giulia d'Amati, Walter Malorni, Massimo Spada, Bernard T. Golding, Lucrezia Gambardella, Roger J. Griffin, Daniele Macchia, Chiara Tommasino, Lucia Gabriele, Maria Buoncervello, Anna Maria Giammarioli, Bruna Cerbelli, and Manuela Alberton
- Subjects
Antifolates ,0301 basic medicine ,antifolates ,antimalarial drugs ,apoptosis ,chemotherapy ,drug repurposing ,melanoma ,oncology ,cancer research ,Cancer Research ,Cell Survival ,Antimalarial Drugs ,Drug repurposing ,Apoptosis ,Antineoplastic Agents ,Mice, SCID ,Pharmacology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Cell Line, Tumor ,medicine ,Chemotherapy ,Animals ,Humans ,Cytotoxic T cell ,Neoplasm Metastasis ,Melanoma ,Cell Proliferation ,Severe combined immunodeficiency ,Cell growth ,business.industry ,Research ,Cell Cycle ,Cell cycle ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Pyrimethamine ,Pyrimidines ,030104 developmental biology ,Oncology ,Caspases ,030220 oncology & carcinogenesis ,Cancer cell ,business ,medicine.drug - Abstract
Background The antimalarial drug Pyrimethamine has been suggested to exert an antitumor activity by inducing apoptotic cell death in cancer cells, including metastatic melanoma cells. However, the dose of Pyrimethamine to be considered as an anticancer agent appears to be significantly higher than the maximum dose used as an antiprotozoal drug. Methods Hence, a series of Pyrimethamine analogs has been synthesized and screened for their apoptosis induction in two cultured metastatic melanoma cell lines. One of these analogs, the Methylbenzoprim, was further analyzed to evaluate cell-cycle and the mechanisms of cell death. The effects of Methylbenzoprim were also analyzed in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model. Results Low dose of Methylbenzoprim was capable of inducing cytotoxic activity and a potent growth-inhibitory effect by arresting cell cycle in S-phase in melanoma cells. Methylbenzoprim was also detected as powerful antineoplastic agents in SCID-mouse although used at very low dose and as a single agent. Conclusions Our screening approach led to the identification of a “low cost” newly synthesized drug (methylbenzoprim), which is able to act as an antineoplastic agent in vitro and in vivo, inhibiting melanoma tumor growth at very low concentrations. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0409-9) contains supplementary material, which is available to authorized users.
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- 2016
43. Solitary nonfamilial desmoplastic trichoepithelioma of the external auditory canal
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Massimo Re, Giuseppe Magliulo, Mario Ciniglio Appiani, and Bruna Cerbelli
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Male ,business.industry ,Desmoplastic trichoepithelioma ,EAC ,surgery ,Carcinoma ,Skull Neoplasms ,Temporal Bone ,Anatomy ,medicine.disease ,Magnetic Resonance Imaging ,Sensory Systems ,Auditory canal ,Young Adult ,Otorhinolaryngology ,Medicine ,Humans ,Neurology (clinical) ,business ,Otologic Surgical Procedures ,Ear Canal - Published
- 2012
44. Melanocytic Nevus of the External Auditory Canal
- Author
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Maria Giovanna Colicchio, Bruna Cerbelli, Mario Ciniglio Appiani, and Giuseppe Magliulo
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Adult ,Nevus, Pigmented ,medicine.medical_specialty ,Skin Neoplasms ,business.industry ,Treatment outcome ,Melanocytic nevus ,medicine.disease ,Dermatology ,Sensory Systems ,Auditory canal ,Treatment Outcome ,Otorhinolaryngology ,medicine ,Humans ,Nevus ,Female ,Neurology (clinical) ,Hearing Loss ,business ,Ear Canal - Published
- 2012
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