Publications by authors named "Sara Franzi"

9 Publications

  • Page 1 of 1

Prognostic Value of 18F-FDG PET/CT Metabolic Parameters in Surgically Treated Stage I Lung Adenocarcinoma Patients.

Clin Nucl Med 2021 May 26. Epub 2021 May 26.

From the Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan Department of Medicine and Surgery, Thoracic Surgery, University of Insubria, Ospedale di Circolo, Varese Nuclear Medicine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan Nuclear Medicine Unit, ASST Settelaghi, Varese, Italy.

Purpose Of The Report: This article aims to explore the prognostic role of 18F-FDG PET/CT metabolic parameters in stage I lung adenocarcinoma patients.

Patients And Methods: One hundred eighty pathological stage I lung adenocarcinoma patients were retrospectively reviewed. Semiquantitative analysis of FDG tumor uptake was performed with TrueD software on the Siemens Leonardo workstation. SUVmean and MTV were calculated using SUV threshold of 41% of SUVmax; the total lesion glycolysis (TLG) was calculated as the product of SUVmean and MTV. Correlation was evaluated using Spearman correlation coefficient. Maximally selected rank statistics was performed to detect the optimal cutoff used for dichotomizing each PET parameter (6.5 for SUVmean, 9.6 for SUVmax, and 19.1 for TLG).

Results: Our main finding was the significant correlation between 18F-FDG PET/CT parameters (SUVmean, SUVmax, and TLG) and disease-free survival in pathologic stage I non-small cell lung cancer. SUVmean has the greatest accuracy in recurrence prediction (integrated area under the curve, 0.803; 95% confidence interval, 0.689-0.918). We run the maximally selected rank statistics to provide the classification of observations in 2 groups by a continuous predictor parameter; the free from recurrence rate was significantly greater in patients with SUVmean ≤6.5, SUVmax ≤9.6, and TLG ≤19.1.

Conclusions: Our research supports the hypothesis that SUVmean, SUVmax, and TLG are well correlated with free from recurrence rate in stage I adenocarcinoma patients, subjected to pulmonary lobectomy. Our findings also indicate these markers as promising prognostic indicators.
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May 2021

Bronchoalveolar Lavage-microRNAs Are Potential Novel Biomarkers of Outcome After Lung Transplantation.

Transplant Direct 2020 May 9;6(5):e547. Epub 2020 Apr 9.

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Primary graft dysfunction, infections, and acute rejection (AR) worsen lung transplantation (LTx) outcome and patient survival. Despite significant efforts, reliable biomarkers of acute lung allograft dysfunction are lacking. To address this issue, we profiled the bronchoalveolar lavage (BAL) miRNome in LTx patients.

Methods: BAL-microRNAs (miRNAs) from 16 patients were collected 7 days (T0), 15 days (T1), and 3 months (T2) after bilateral LTx and profiled on low-density array. Unsupervised and supervised analyses were used to identify miRNAs associated with clinical features, pneumonia, or AR. Prognostic markers were identified using the Cox model. Targeted signaling pathways were predicted in silico. A second series of 11 patients were used to validate AR-associated miRNAs.

Results: Variation in BAL-miRNAs was associated with acute lung allograft dysfunction. Increased levels of miR-23b-3p at T2 were detected in patients with pneumonia, whereas let-7f-5p, miR-146b-3p, miR-22-5p, miR-29c-5p, miR-362-5p, and miR-452-5p were upregulated at T2 in patients with AR. miR-148b-5p and miR-744-3p distinguished LTx patients with AR in both cohorts. Low miR-148b-5p and high miR-744-3p expression levels were significantly associated with a shorter time to AR either within the first year after LTx or during follow-up. Combination of the 2 miRNAs identified LTx patients with higher AR risk independently of clinical variables.

Conclusions: Our data provide new insights into the roles of BAL-miRNAs in regulating the pulmonary environment after transplantation and suggest that these miRNAs could serve as biomarkers of early- or mid-stage events. If validated, these findings could pave the way to a personalized clinical approach in LTx patients.
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May 2020

Epstein-Barr virus in tumor-infiltrating B cells of myasthenia gravis thymoma: an innocent bystander or an autoimmunity mediator?

Oncotarget 2017 Nov 8;8(56):95432-95449. Epub 2017 Sep 8.

Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico "Carlo Besta", 20133 Milan, Italy.

The thymus plays a key role in myasthenia gravis (MG), a B cell-mediated autoimmune disorder affecting neuromuscular junction. Most MG patients have thymic abnormalities, including hyperplasia and thymoma, a neoplasm of thymic epithelial cells. Epstein-Barr virus (EBV) is associated with autoimmune diseases and tumors. Recently, we showed EBV persistence and reactivation in hyperplastic MG thymuses, suggesting that EBV might contribute to intra-thymic B cell dysregulation in MG patients. Here, we investigated EBV involvement in thymoma-associated MG, by searching for EBV markers in MG (n=26) and non-MG (n=14) thymomas. EBV DNA and EBV-encoded small nuclear RNA (EBER) 1 transcript were detected in 14/26 (53.8%) and 22/26 (84.6%) MG thymomas, and only in 3 of 14 (21.4%) non-MG thymomas. Latent EBNA2 and late gp350/220 lytic transcripts were undetectable in all, but one, thymomas, and early lytic BZLF1 transcript was absent in all samples, suggesting that early infection events and EBV reactivation were very rare in thymomas. EBER1 and 2-positive cells were detected in MG, but not in non-MG, thymomas, as well as cells expressing EBV latency proteins (EBNA1, LMP1, LMP2A), that were mainly of B cell phenotype, indicating EBV association with MG rather than with thymoma. Toll-like receptor (TLR) 3 transcriptional levels were higher in MG than non-MG thymomas and positively correlated with EBER1 levels, suggesting a role for EBERs in TLR3 activation. Our findings show that EBV is commonly present in thymoma-infiltrating B cells of myasthenic patients, indicating a contribution of EBV to B cell-mediated autoreactivity in MG associated with thymic tumor.
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November 2017

A novel ABCC6 haplotype is associated with azathioprine drug response in myasthenia gravis.

Pharmacogenet Genomics 2017 02;27(2):51-56

aNeurology IV - Neuroimmunology and Neuromuscular Diseases Unit bBioinformatics Unit, IRCCS Foundation Neurological Institute 'Carlo Besta' cGenopolis Consortium, Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy.

Objective: We investigated the association of single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes and transporters (DMETs) with the response to azathioprine (AZA) in patients affected by myasthenia gravis (MG) to determine possible genotype-phenotype correlations.

Patients And Methods: Genomic DNA from 180 AZA-treated MG patients was screened through the Affymetrix DMET platform, which characterizes 1931 SNPs in 225 genes. The significant SNPs, identified to be involved in AZA response, were subsequently validated by allelic discrimination and direct sequencing. SNP analysis was carried out using the SNPassoc R package and the haploblocks were determined using haploview software.

Results: We studied 127 patients in the discovery phase and 53 patients in the validation phase. We showed that two SNPs (rs8058694 and rs8058696) found in ATP-binding cassette subfamily C member 6, a subfamily member of ATP-binding cassette genes, constituted a new haplotype associated with AZA response in MG patients in the discovery cohort (P=0.011; odds ratio: 0.40; 95% confidence interval: 0.20-0.83) and in the combined cohort (P=0.04; odds ratio: 1.58).

Conclusion: These findings highlight the role that the ATP-binding cassette subfamily C member 6 haplotype may play in AZA drug response. In view of the significant effects and AZA intolerance, these novel SNPs should be taken into consideration in pharmacogenetic profiling for AZA.
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February 2017

Increased expression of Toll-like receptors 7 and 9 in myasthenia gravis thymus characterized by active Epstein-Barr virus infection.

Immunobiology 2016 Apr 12;221(4):516-27. Epub 2015 Dec 12.

Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico "Carlo Besta", Via Celoria 11, 20133 Milan, Italy. Electronic address:

Considerable data implicate the thymus as the main site of autosensitization to the acetylcholine receptor in myasthenia gravis (MG), a B-cell-mediated autoimmune disease affecting the neuromuscular junction. We recently demonstrated an active Epstein-Barr virus (EBV) infection in the thymus of MG patients, suggesting that EBV might contribute to the onset or maintenance of the autoimmune response within MG thymus, because of its ability to activate and immortalize autoreactive B cells. EBV has been reported to elicit and modulate Toll-like receptor (TLR) 7- and TLR9-mediated innate immune responses, which are known to favor B-cell dysfunction and autoimmunity. Aim of this study was to investigate whether EBV infection is associated with altered expression of TLR7 and TLR9 in MG thymus. By real-time PCR, we found that TLR7 and TLR9 mRNA levels were significantly higher in EBV-positive MG compared to EBV-negative normal thymuses. By confocal microscopy, high expression levels of TLR7 and TLR9 proteins were observed in B cells and plasma cells of MG thymic germinal centers (GCs) and lymphoid infiltrates, where the two receptors co-localized with EBV antigens. An increased frequency of Ki67-positive proliferating B cells was found in MG thymuses, where we also detected proliferating cells expressing TLR7, TLR9 and EBV antigens, thus supporting the idea that EBV-associated TLR7/9 signaling may promote abnormal B-cell activation and proliferation. Along with B cells and plasma cells, thymic epithelium, plasmacytoid dendritic cells and macrophages exhibited enhanced TLR7 and TLR9 expression in MG thymus; TLR7 was also increased in thymic myeloid dendritic cells and its transcriptional levels positively correlated with those of interferon (IFN)-β. We suggested that TLR7/9 signaling may be involved in antiviral type I IFN production and long-term inflammation in EBV-infected MG thymuses. Our overall findings indicate that EBV-driven TLR7- and TLR9-mediated innate immune responses may participate in the intra-thymic pathogenesis of MG.
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April 2016

Innate immunity in myasthenia gravis thymus: pathogenic effects of Toll-like receptor 4 signaling on autoimmunity.

J Autoimmun 2014 Aug 4;52:74-89. Epub 2014 Jan 4.

Neurology IV Unit, Neurological Institute 'Carlo Besta', Via Celoria 11, 20133 Milan, Italy. Electronic address:

The thymus is the main site of immune sensitization to AChR in myasthenia gravis (MG). In our previous studies we demonstrated that Toll-like receptor (TLR) 4 is over-expressed in MG thymuses, suggesting its involvement in altering the thymic microenvironment and favoring autosensitization and autoimmunity maintenance processes, via an effect on local chemokine/cytokine network. Here, we investigated whether TLR4 signaling may favor abnormal cell recruitment in MG thymus via CCL17 and CCL22, two chemokines known to dictate immune cell trafficking in inflamed organs by binding CCR4. We also investigated whether TLR4 activation may contribute to immunodysregulation, via the production of Th17-related cytokines, known to alter effector T cell (Teff)/regulatory T cell (Treg) balance. We found that CCL17, CCL22 and CCR4 were expressed at higher levels in MG compared to normal thymuses. The two chemokines were mainly detected around medullary Hassall's corpuscles (HCs), co-localizing with TLR4(+) thymic epithelial cells (TECs) and CCR4(+) dendritic cells (DCs), that were present in higher number in MG thymuses compared to controls. TLR4 stimulation in MG TECs increased CCL17 and CCL22 expression and induced the production of Th17-related cytokines. Then, to study the effect of TLR4-stimulated TECs on immune cell interactions and Teff activation, we generated an in-vitro imaging model by co-culturing CD4(+) Th1/Th17 AChR-specific T cells, naïve CD4(+)CD25(+) Tregs, DCs and TECs from Lewis rats. We observed that TLR4 stimulation led to a more pronounced Teff activatory status, suggesting that TLR4 signaling in MG thymic milieu may affect cell-to-cell interactions, favoring autoreactive T-cell activation. Altogether our findings suggest a role for TLR4 signaling in driving DC recruitment in MG thymus via CCL17 and CCL22, and in generating an inflammatory response that might compromise Treg function, favoring autoreactive T-cell pathogenic responses.
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August 2014

Type 1 interferons inhibit myotube formation independently of upregulation of interferon-stimulated gene 15.

PLoS One 2013 4;8(6):e65362. Epub 2013 Jun 4.

Children's Hospital Informatics Program, Boston Children's Hospital, Boston, Massachusetts, USA.

Introduction: Type 1 interferon (IFN)-inducible genes and their inducible products are upregulated in dermatomyositis muscle. Of these, IFN-stimulated gene 15 (ISG15) is one of the most upregulated, suggesting its possible involvement in the pathogenesis of this disease. To test this postulate, we developed a model of type 1 IFN mediated myotube toxicity and assessed whether or not downregulation of ISG15 expression prevents this toxicity.

Methods: Mouse myoblasts (C2C12 cell line) were cultured in the presence of type 1 or type 2 IFNs and ISG15 expression assessed by microarray analysis. The morphology of newly formed myotubes was assessed by measuring their length, diameter, and area on micrographs using imaging software. ISG15 expression was silenced through transfection with small interference RNA.

Results: Type 1 IFNs, especially IFN-beta, increased ISG15 expression in C2C12 cells and impaired myotube formation. Silencing of ISG15 resulted in knockdown of ISG15 protein, but without phenotypic rescue of myotube formation.

Discussion: IFN-beta affects myoblast differentiation ability and myotube morphology in vitro.These studies provide evidence that ISG15, which is highly upregulated in dermatomyositis muscle, does not appear to play a key role in IFN-beta-mediated C2C12 myoblast cell fusion.
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September 2014

B cell lymphoma (Bcl)-2 protein is the major determinant in bcl-2 adenine-uridine-rich element turnover overcoming HuR activity.

J Biol Chem 2009 Jul 11;284(31):20946-55. Epub 2009 Jun 11.

Department of Pharmacology, Università degli Studi di Milano, 20129 Milan.

In the 3'-untranslated region, the destabilizing adenine-uridine (AU)-rich elements (AREs) control the expression of several transcripts through interactions with ARE-binding proteins (AUBPs) and RNA degradation machinery. Although the fundamental role for AUBPs and associated factors in eliciting ARE-dependent degradation of cognate mRNAs has been recently highlighted, the molecular mechanisms underlying the specific regulation of individual mRNA turnover have not yet been fully elucidated. Here we focused on the post-transcriptional regulation of bcl-2 mRNA in human cell lines under different conditions and genetic backgrounds. In the context of an AUBPs silencing approach, HuR knockdown reduced the expression of endogenous bcl-2, whereas unexpectedly, a bcl-2 ARE-reporter transcript increased significantly, suggesting that HuR expression has opposite effects on endogenous and ectopic bcl-2 ARE. Moreover, evidence was provided for the essential, specific and dose-dependent role of the Bcl-2 protein in regulating the decay kinetics of its own mRNA, as ascertained by a luciferase reporter system. Altogether, the data support a model whereby the Bcl-2 protein is the major determinant of its own ARE-dependent transcript half-life in living cells and its effect overcomes the activity of ARE-binding proteins.
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July 2009

Stabilization of cellular mRNAs and up-regulation of proteins by oligoribonucleotides homologous to the Bcl2 adenine-uridine rich element motif.

Mol Pharmacol 2007 Feb 31;71(2):531-8. Epub 2006 Oct 31.

Department of Pharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy.

Adenine-uridine rich elements (AREs) play an important role in modulating mRNA stability, being the target site of many ARE-binding proteins (AUBPs) that are involved in the decay process. Three 26-mer 2'-O-methyl oligoribonucleotides (ORNs) homologous to the core region of ARE of bcl2 mRNA have been studied for decoy-aptamer activity in UV cross-linking assays. Sense-oriented ORNs competed with the ARE motif for the interaction with both destabilizing and stabilizing AUBPs in cell-free systems and in cell lines. Moreover, ORNs induced mRNA stabilization and up-regulated both Bcl2 mRNA and protein levels in the cells. Bcl2 ORNs stabilized other ARE-containing transcripts and up-regulated their expression. These results indicate that Bcl2 ORNs compete for AUBP-ARE interactions independently of ARE class and suggest that in the cell, the default labile status of ARE-containing mRNAs depends on the combined interaction of such transcripts with destabilizing AUBPs.
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February 2007