Silvio Roncella - Academia.edu (original) (raw)

Papers by Silvio Roncella

Oligonucleotides, 2005

In Burkitt's lymphoma (BL) cells c-myc is often translocated in proximity to the E enhancer of th... more In Burkitt's lymphoma (BL) cells c-myc is often translocated in proximity to the E enhancer of the Ig gene locus. This translocation causes c-myc hyperexpression and an increase in the cells' proliferative capacity. A peptide nucleic acid (PNA) complementary to enhancer E intronic sequence (PNAE), linked to a nuclear localization signal (NLS), selectively and specifically blocks the expression of the c-myc oncogene under E control in vitro, suggesting potential therapeutic use. To explore this issue further, we have determined the pharmacokinetics of 14 C-labeled PNAE in SCID mice where a human tumor is established by inoculation of cells from a BL cell line. The data demonstrate that the compound has a relatively long life in vivo in tissues and, in particular, in BL tumor mass. Furthermore, in this animal model, PNAE shows low or no toxicity. All these results are in favor of a successful preclinical application in a BL human tumor animal model of a PNA targeting a regulatory, nontranscribed DNA sequence that can selectively inhibit the hyperexpression of a translocated gene linked to neoplastic cell expansion.

Molecular and Cellular Probes, 1996

Epstein-Barr virus (EBV) type and strain variations were examined using both lymphoblastoid cell ... more Epstein-Barr virus (EBV) type and strain variations were examined using both lymphoblastoid cell lines (LCLs), spontaneously derived in vitro from peripheral blood mononuclear cells (PBMC) of 15 HIV-1-seropositive individuals; and SCID mouse tumours induced by inoculation of PBMC from 11 healthy human donors (Hu-SCID tumours). Polymerase chain reaction (PCR) analysis disclosed that all but one of the 26 EBV + samples harboured EBV nuclear antigen (EBNA) 2 and 3C type A virus. On the other hand, single strand conformation polymorphism (SSCP) analysis using Epstein-Barr encoded RNA (EBER) specific primers detected an AG876-like (type B) band pattern in 21 of the 26 EBV + samples. Three Hu-SCID tumours scored as B95.8-like (type A), and two showed neither a type A nor a type B SSCP migration pattern. Sequence analysis of the amplified EBER fragments confirmed the PCR-SSCP findings; moreover, additional mutations were present not only in the two EBV + samples with anomalous SSCP pattern, but also in two other samples with a standard SSCP profile. Thus, EBER analysis did not correlate with EBNA typing, and appeared to be unsuitable for EBV type assessment. Latent membrane protein (LMP) analysis disclosed, on the whole, sever size variants: as expected, the differences were due to the variable numbers of a 33-bp repeat in the amplified fragment, as assessed by direct sequencing. The broader variability detected by LMP analysis should prove more useful than typing for assessing the presence of single and/or mixed variants resulting from EBV reactivation and/or reinfection.

Journal of Neuro-Oncology, 2008

Leptomeningeal (LM) carcinomatosis is an increasing clinical complication in patients with advanc... more Leptomeningeal (LM) carcinomatosis is an increasing clinical complication in patients with advanced breast cancer (BC). The LM carcinomatosis diagnostic procedures rely mainly on cerebrospinal fluid (CSF) cytology, although both the amount of CSF and the number of malignant cells remain limiting factors. Therefore, efforts should be made to design new highly sensitive diagnostic tools to detect malignant cells in CSF of BC patients with LM carcinomatosis. In this study, the human Mammaglobin (hMAM) mRNA amplification by RT-PCR was employed to detect metastatic cells in CSF and thus, to diagnose LM carcinomatosis in a BC patient. Our data demonstrate that hMAM transcripts are expressed in the CSF of a BC patient with LM carcinomatosis, hence making RT-PCR for hMAM a potentially suitable test to identify occult BC cells in the brain.

Genes, Chromosomes and Cancer, 1993

We have analyzed the type of MYC/IG heavy‐chain locus (IGH) rearrangement present in 15 patients ... more We have analyzed the type of MYC/IG heavy‐chain locus (IGH) rearrangement present in 15 patients affected by t(8; 14)‐positive primary Burkitt's lymphoma or acute lymphoblastic leukemia of the L3 type in an attempt to map in detail the locations of the chromosome 8 and chromosome 14 breakpoints. The almost constant position of the chromosome 8 breakpoint (within or immediately 5′ of the MYC gene) together with two distinct clusters of breakpoints on chromosome 14 resulted in two main types of MYC/IGH (present in 12 of 15 cases). In the first type (six cases), the MYC gene or at least its coding portion was joined with the JH region on chromosome 14, whereas in the second, present in another six cases, the MYC gene and the Cαl region were juxtaposed. Physical linkage between the translocated MYC and a known enhancer element of the IGH locus is the common feature in the two types of rearrangement, suggesting that a high‐level constitutive expression plays a prominent role in MYC a...

CHEST Journal, 2012

Soluble mesothelin-related peptides (SMRP) are an FDA approved biomarker for the diagnosis and mo... more Soluble mesothelin-related peptides (SMRP) are an FDA approved biomarker for the diagnosis and monitoring of pleural malignant mesothelioma (MPM). We report the SMRP levels in pleural fluid from a cohort of Italian patients and its utility in clinical management of MPM pleural effusions (MPM-PE). METHODS: We evaluated SMRP in 52 MPM-PE (35 epithelioid, 9 sarcomatoid, 4 biphasic, 2 desmoplastic, 2 papillary), 129 benign PE (B-PE) and 94 non-MPM pleural metastasis (Mts-PE) by means of the MesoMark ELISA kit. The diagnostic performance parameters were estimated through analysis of the ROC curve and the Youden's index was applied to obtain the biomarker's cutoff level of maximum discrimination. For each cut off, sensitivity (Se) and specificity (Sp) were calculated. The degree of correlation and P value were calculated using the diagnostic odds ratio (DOR) and the Chi-square test, respectively. Comparison between SMRP detection and cytology was also performed. RESULTS: The median SMRP levels was significantly higher in MPM-PE (28.2 nM) than in B-PE (3.2 nM) or Mts-PE (3.8 nM). MPM-PE yielded an AUC of 84.5 (p<0.001) vs B-PE and an AUC of 79.6 (p<0.001) vs Mts-PE. The cut off level of maximum discrimination between MPM vs each patient groups was 9.30 nmol/L. At this cut off value, we established Se=75%, Sp=93% for MPM-PE vs B-PE and SP=81% for MPM-PE vs Mts-PE. We found SMRPpositive cases (≥ cut off) in 38/52 (73.1%) MPM-PE, in 9/129 (7.0%) B-PE (DOR=40, p<0.001) and in 18/94 (19.1%) Mts-PE (DOR=13, p< 0.001). In 38/52 PE, with SMPR levels ≥ cut off, cytology was found positive in 11/38 (28.9%), negative in 20/38 (52.6%) and in 7/38 (18.4%) was considered suspicious. Moreover, in 4/15 (26.7%) cases of cytology-positive MPM-PE, the levels of SMPR resulted negative. CONCLUSIONS: SMPR detection in MPM-PE may provide additional diagnostic value to cytology. Combination of SMPR and cytology may increase diagnostic yield if both tests are performed together. CLINICAL IMPLICATIONS: SMPR analysis may be incorporated into clinical practice of MPM-PE in patients with suspected malignant mesothelioma.

British Journal of Haematology, 1993

... respectively: Dr Alberto Mantovani, Istituto di Ricerche Farmacologiche Mario Negri, Milano. ... more ... respectively: Dr Alberto Mantovani, Istituto di Ricerche Farmacologiche Mario Negri, Milano. for the gift of the WEHI 164 murine sarcoma cell line: Dr Maurizio Viale. Service of Pharmacology, National Institute for Cancer Research, Genova, Italy, for help with the TNFP assays. ...

Blood, 1997

Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHL), a major... more Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHL), a major source of morbidity and mortality among human immunodeficiency virus (HIV)-infected individuals, are derived from B cells and are classified into two major categories, Burkitt's lymphoma (BL) and diffuse large cell lymphoma (DLCL). Anaplastic large cell lymphoma (ALCL) and body-cavity-based lymphoma (BCBL) represent less frequent AIDS-NHL types. The molecular pathogenesis of AIDS-NHL is characterized by distinct genetic pathways, including chromosomal rearrangements of c-MYC and BCL-6 in AIDS-BL and AIDS-DLCL, respectively. In addition to gross rearrangements, recent evidence has suggested that BCL-6 may also be affected by mutations of the gene 5' noncoding regions. Here we have investigated the distribution of BCL-6 mutations in a panel representative of all the AIDS-NHL subtypes. Forty-three AIDS-NHL were analyzed for mutations in the first exon-first intron boundary region o...

Cancer immunology, immunotherapy : CII, Aug 20, 2016

CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, w... more CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, whereas much less is known about the immunoregulatory role of its soluble isoform (sCTLA-4). No data are available on CTLA-4 expression and prognostic impact in malignant pleural mesothelioma (MPM). We investigated, by immunohistochemistry, CTLA-4 expression in tumor tissues and, by ELISA, sCTLA-4 levels in sera and matched pleural effusions from 45 MPM patients. Prognostic effect of CTLA-4 expression on overall survival (OS) was assessed through Cox regression and prognostic significance expressed as death rate ratio (HR). We found that 56.0 % of MPM tissues expressed CTLA-4 with variable intensity and percentage of positive cells estimated by the immunoreactive score. sCTLA-4 levels were significantly higher in sera (S-sCTLA-4) than in pleural effusions (PE-sCTLA-4) (geometric mean ratio = 2.70, P value = 0.020). CTLA-4 expression at the tissue level was higher in the epithelioid histol...

International Journal of Oncology, 1997

Six non-small cell lung cancer (NSCLC) cell lines (A-549, Ca-Lu-6, SK-Lu-1, Ca-Lu-1, SK-Mes-1 and... more Six non-small cell lung cancer (NSCLC) cell lines (A-549, Ca-Lu-6, SK-Lu-1, Ca-Lu-1, SK-Mes-1 and LX-1) were studied to assess the presence of multiple concomitant alterations of different oncogenes (K-ras, bcl-2) and tumor suppressor genes (p53, Rb) in NSCLC. K-ras (exon 1) and p53 (exons 5-8) gene mutations were determined via a PCRbased-DGGE (Denaturing Gradient Gel Electro-phoresis) and by sequencing approach. Different mutations were found in the 1st exon of K-ras gene in 5 of 6 cell lines examined. Five of six cell lines contained K-ras mutations at codon 12 (A-549, SK-Lu-1, LX-1) or codon 13 (SK-Mes-1, Ca-Lu-1). In addition, 5 of 6 cell lines showed p53 mutations of exon 8 (SK-Mes-1, Ca-Lu-1 cod. 280; LX-1 cod. 273) or exon 6 (Ca-Lu-6 cod. 196; SK-Lu-1 cod. 193). In 4 of these cell lines, p53 protein nuclear expression was also confirmed with DO-7 mAb immunocytochemistry. Expression of cytoplasmic bcl-2 protein, by anti-bcl-2 mAb flow cytometric analysis, was found in A-549, Ca-Lu-1, SK-Lu-1, SK-Mes-1 cell lines. In contrast, RT-PCR analysis of Rb gene could not identify any change in the cell lines examined. In conclusion, most NSCLC cell lines tested displayed concomitant multiple oncogene/tumor suppressor gene alterations.

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Pathologica, 2003

In this report, we describe a case of poorly differentiate myoepithelial cell rich carcinoma in w... more In this report, we describe a case of poorly differentiate myoepithelial cell rich carcinoma in with morphological findings of large poligonal nests with festoon-like pattern sometimes showing central necrosis, reminiscent of a comedo-like pattern and numerous mitoses. Immunohistochemical staining shows positive reaction for cytokeratin AE/1, CAM 5.2, 34 beta E12, vimentin, smooth muscle actin, EMA, S100 protein and oncogene cERB.b2 and negative for estrogen, progesterone, GFAP and chromogranin. Moreover, this carcinoma show the expression of the mammaglobin mRNA, a highly specific marker of breast epithelial cells that it is not expressed in all breast carcinoma.

Nutrition, 1996

As a complex syndrome, cachexia has different clinical manifestations; anorexia appears to be one... more As a complex syndrome, cachexia has different clinical manifestations; anorexia appears to be one of the most frequent findings, together with weight loss. Anorexia is the cause and partly the consequence of metabolic changes and of progressive undernourishment. In cancer cachexia, weight loss is associated with a marked decrease of food intake and severe alteration of body composition. Malnourished cancer patients show a marked loss of adipose tissue and protein mass with BIA evidence of decreased body cell mass and expansion of extracellular water. The mechanisms of anorexia and cachexia are still a matter of debate, but the possible involvement of cytokines in the pathogenesis of this syndrome has opened up new possibilities for its understanding and treatment. As a result of the multifactorial etiology of cancer caehexia/anorexia, therapies that stimulate appetite and promote greater food intake, coupled with factors that influence metabolism and cytokine production may be an optimal therapeutic strategy. Of particular interest appears to be the possible role played by fish oil in antagonizing the negative effects of cytokines. Future research in this field will help clinicians develop new methods to treat patients who have diseaseinduced starvation and wasting.

Leukemia & Lymphoma, 1993

Two cell lines were originated from the peripheral blood (PB-LAM) and bone-marrow (BM-LAM) of a p... more Two cell lines were originated from the peripheral blood (PB-LAM) and bone-marrow (BM-LAM) of a patient with Burkitt-type acute lymphoblastic leukemia and AIDS. 26 and 7 clones were isolated from PB-LAM and BM-LAM respectively by limiting dilution. All of these had surface IgM lambda and the CD10 marker with low to absent CD23, CD30, CD39 and surface adhesion molecules. Furthermore, they shared the same chromosomal abnormalities (trisomy 7 and t(8;14) translocation) and the same rearrangements of immunoglobulin L and H chain and of c-myc gene loci. These features are those most frequently found in Burkitt's lymphoma (BL) cells and were different from those of the parental cell lines, which, besides cells identical to those of the malignant clones, also contained normal lymphoblastoid cells. Therefore, the cloning procedure used selected for the growth of cells with malignant features. EBV latent antigens were detected in all clones by Western blotting and their pattern of expression resembled that usually observed in BL cells. All the clones were positive for the EBV genome by Southern blotting and had monomorphic EBV-fused termini as determined by using cDNA probes specific for sequences at either end of the viral genome. However, the clones derived from PB-LAM had EBV fused termini of a different size from that of the clones derived from BM-LAM. The presence of different EBV-fused termini in otherwise monoclonal malignant cells indicate that EBV infection was possibly a late event in lymphomagenesis following rearrangement of the c-myc and the Ig gene loci.

International Journal of Cancer, 1990

We describe a human lymphoblastoid cell line (LCL), called ZS, that originated spontaneously from... more We describe a human lymphoblastoid cell line (LCL), called ZS, that originated spontaneously from the cultures of gamma‐irradiated (50 Gy) peripheral‐blood mononuclear cells of a normal donor. When injected subcutaneously in sublethally irradiated, splenectomized and anti‐asialo‐GM1‐treated nude mice, ZS cells invaded the lymph nodes, that appeared 10 to 50‐fold enlarged in all of the mice tested. Furthermore, ZS cells expressed a typical T‐cell surface structure, the CD2 molecule, detectable by a variety of different anti‐CD2 monoclonal antibodies (MAbs). However, other T‐cell markers were not found, with the possible exception of a truncated messenger of the β chain of the T‐cell receptor and ZS cells could be identified as B cells since they (i) expressed a battery of markers of the resting and activated B cells, (ii) displayed a monoclonal rearrangement of the lgH chain locus and (iii) synthesized lgM K molecules.The Epstein‐Barr virus (EBV) genome was detected in ZS cells in ap...

Cellular Immunology, 1999

Using immunofluorescence, RT-PCR, and Western blotting, we have demonstrated the ability of human... more Using immunofluorescence, RT-PCR, and Western blotting, we have demonstrated the ability of human B cells to express CD4. In each of the 10 lymphoblastoid cell lines (LCL) tested there was variable, but definite, proportion of CD4-positive B cells. Expression of CD4 was related to the cell cycle; CD4 was expressed in the G1 phase and continued at later phases of the cell cycle. CD4 was in part internalized and degraded by the LCL B cells. Surface CD4 was associated to lck and its crosslinking resulted in tyrosine phosphorylation. Additional experiments conducted on freshly prepared tonsillar B cells demonstrated that CD4 was expressed by large activated B cells, but not by small resting B cells. However, not all the activated tonsillar B cells had surface CD4 since germinal center cells were CD4-negative. Crosslinking of CD4 on LCL or on tonsillar activated B cells resulted in apoptosis in vitro, a finding that indicates the capacity of CD4 to deliver functional signals to B cells and to play a regulatory function in their physiology. Exposure of CD4 expressing B cells to gp120 under conditions that resulted in CD4 crosslinking also caused apoptosis suggesting some implications for the pathophysiology of AIDS.

Cancer Genetics and Cytogenetics, 1992

We present the case of a 4-day-old boy with acute lymphoblastic leukemia showing at onset a karyo... more We present the case of a 4-day-old boy with acute lymphoblastic leukemia showing at onset a karyotype 46,XY,t(4;11)(q21;q23). At relapse an additional change, add(2), was present. Molecular analysis showed the same immunoglobulin rearrangement both at onset and at relapse, but immunohistochemical analysis revealed some cells having myeloid features. A continuous cell line derived from the leukemic blasts of the patient presented typical monoblastic features.

British Journal of Haematology, 1998

The pathogenesis of AIDS‐related non‐Hodgkin's lymphomas (AIDS‐NHL) involves accumulation of ... more The pathogenesis of AIDS‐related non‐Hodgkin's lymphomas (AIDS‐NHL) involves accumulation of genetic lesions, stimulation and selection by antigen, as well as infection by viruses. Deregulation of cytokine loops has also been proposed to contribute to AIDS‐NHL development, although data are available only for a limited number of cytokines. In this study we have utilized a panel of AIDS‐NHL cell lines to investigate in detail the pattern of tumour expression and production of a wide spectrum of cytokines. The cytokines investigated included interleukin (IL)‐1α, IL‐1β, IL‐2, IL‐3, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, IL‐10, IL‐13, TNFα, TNFβ, IFNγ, TGFβ2, G‐CSF, GM‐CSF and SCF. The AIDS‐NHL cell lines utilized were representative of both AIDS‐related Burkitt lymphoma (AIDS‐BL) and AIDS‐related body cavity‐based lymphoma (AIDS‐BCBL). Overall, AIDS‐NHL were found to produce IL‐6, IL‐10 and TNFβ, although with different patterns depending upon the biological features of the tumour. Producti...

Diagnostics, 2021

A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker for diagnosis of p... more A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker for diagnosis of pleural mesothelioma (PM) and the most used for monitoring treatment. Radiological assessment of PM, based on modified RECIST (mRECIST) criteria, is challenging. This pilot study was designed to evaluate whether SMRP levels correlated over time with mRECIST score. Serial serum samples from PM patients were collected and SMRP levels were measured and compared with the mRECIST score obtained through centralized CT scans by blinded review. The within-patient SMRP-mRECIST relationship over time was estimated through a normal random-effects regression approach applied to the log-transformed mRECIST score. Overall, 58 PM patients were included (46 males and 12 females) with a median age at diagnosis of 67 years (min–max = 48–79), 44 (76%) with epithelioid and 14 (24%) with non-epithelioid histology. The total number of SMRP measurements and CT scans considered for analysis was 183. There was a ...

Journal of Thoracic Oncology, 2019

European Respiratory Journal, Sep 1, 2011

Pleural effusions (PE) are frequently the presenting symptom of neoplastic disease. Serum mesothe... more Pleural effusions (PE) are frequently the presenting symptom of neoplastic disease. Serum mesothelin related peptide (SMRP) is a new biomarker for the diagnosis of mesothelioma. The aim of this study was to investigate the diagnostic significance of mesothelin in PE of unknown origin. Pleural fluid, obtained from 104 patients between March 2008 and October 2009, were compared with histology of pleural biopsy taken during consecutive medical thoracoscopy. We had: 34 PE from mesotheliomas (25 epitheliomorphic, 9 sarcomatoid), 35 from pleural metastasis, 35 from benign diseases. SMRP concentrations was obtained using an ELISA test. SMRP levels in PE were significantly higher in patients with epitheliomorphic mesothelioma (mean ±SD, 46,55 nM ± 44,29) than in patients with sarcomatoid mesothelioma (16.11 nM± 25.02) (p=0.061), pleural metastasis (7.52 nM± 10.77) (p Pleural SMRP levels higher than 19.6 nM were observed in 18/25 (72%) patients with epiteliomorphic mesothelioma, in 5/35 (14.3%) with pleural metastasis, in 2/9 (22.2%) with sarcomatoid mesothelioma, 1/35 (2.9%) with benign diseases. SMRP has the potential to add clinically significant information in the work-up of patients with a PE of unknown origin.