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Roselli M.,University of Rome Tor Vergata | Riondino S.,University of Rome Tor Vergata | Mariotti S.,University of Rome Tor Vergata | La Farina F.,Ceglie Messapica Hospital | Guadagni F.,InterInstitutional Multidisciplinary Biobank BioBIM
Cancer and Metastasis Reviews | Year: 2014

Venous thromboembolism (VTE) is a frequent complication of lung cancer and its treatment, especially in the advanced stages of disease. The risk of a pro-thrombotic state might increase through the activation of hemostasis, occurring both via the induction of a pro-coagulant activity and with platelet involvement, ultimately leading to the development of metastases. Despite the acknowledgement of an increased thrombophilic condition in cancer patients, and the experimental evidence that heparin compounds may have direct anticancer benefits, there is no univocal consent regarding VTE prevention in cancer outpatients receiving therapy. Thus, many authors highlighted the need for the development of stratification techniques to identify at-risk patients who might benefit from thromboprophylaxis. Clinical risk models were developed and validated, in order to assign high-risk patients to a proper thromboprophylaxis regimen that, however, might not be justified in all clusters. Besides, efforts have been devoted to identify candidate biomarkers that may be used in VTE risk assessment, although none has been recognized, so far, as a predictor for VTE in lung cancer patients. In this review, we will summarize the latest information concerning this very controversial topic, with focus on some of the proposed strategies to select the appropriate patients for prophylaxis. © 2014 Springer Science+Business Media.


Betsou F.,IBBL Integrated Biobank of Luxembourg | Gunter E.,Specimen Solutions LLC | Clements J.,Queensland University of Technology | De Souza Y.,University of California at San Francisco | And 7 more authors.
Journal of Molecular Diagnostics | Year: 2013

Control of biospecimen quality that is linked to processing is one of the goals of biospecimen science. Consensus is lacking, however, regarding optimal sample quality-control (QC) tools (ie, markers and assays). The aim of this review was to identify QC tools, both for fluid and solid-tissue samples, based on a comprehensive and critical literature review. The most readily applicable tools are those with a known threshold for the preanalytical variation and a known reference range for the QC analyte. Only a few meaningful markers were identified that meet these criteria, such as CD40L for assessing serum exposure at high temperatures and VEGF for assessing serum freeze-thawing. To fully assess biospecimen quality, multiple QC markers are needed. Here we present the most promising biospecimen QC tools that were identified. Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology.


Ferroni P.,University San Raffaele | Ferroni P.,Interinstitutional Multidisciplinary BioBank BioBIM | Palmirotta R.,University San Raffaele | Palmirotta R.,Interinstitutional Multidisciplinary BioBank BioBIM | And 8 more authors.
Thrombosis and Haemostasis | Year: 2016

Among the possible genetic contributors to cancer-related venous thromboembolism (VTE), vascular endothelial growth factor (VEGFA) could play an important role, as an imbalance of the VEGFA system (either disease-related or drug-induced) may result in a disturbance of vascular homeostasis. Thus, this study was designed to investigate the predictive role of eight different VEGFA gene promoter single nucleotide polymorphisms (SNPs) for a first VTE episode in cancer out-patients undergoing chemotherapy. To this purpose, VEGFA gene promoter polymorphisms were analysed in 297 cancer patients using polymerase chain reaction amplification and direct DNA sequencing analysis. One hundred forty unrelated healthy subjects from the same geographical area were also analysed in order to evaluate and compare genotype/haplotype frequencies in our ethnicity. VTE occurred in 26 (9 %) of cancer patients with a median time-to-event of 3.4 months. Association analyses showed that-1154G/A polymorphism was significantly associated with the risk of chemotherapy-triggered VTE, with the A allele exerting a protective role both in the overall population (hazard ratio [HR]: 0.21; 95 % confidence interval [CI]: 0.07-0.58) or in bevacizumab-treated metastatic patients (HR: 0.09, 95 %CI: 0.01-0.86) in whom VEGFA-1154AA genotype also conferred a reduced risk of early progression (HR: 0.58, 95 %CI: 0.34-0.98). These results suggest that VEGFA may represent a candidate gene contributing to VTE development in chemotherapy treated cancer patients and that-1154G/A SNP might provide useful clinical information on the efficacy and toxicity of bevacizumab in metastatic patients. Validation studies are needed for translation into clinical practice. © Schattauer 2016.


Roselli M.,University of Rome Tor Vergata | Fernando R.I.,U.S. National Cancer Institute | Guadagni F.,Interinstitutional Multidisciplinary Biobank BioBIM | Spila A.,Interinstitutional Multidisciplinary Biobank BioBIM | And 10 more authors.
Clinical Cancer Research | Year: 2012

Purpose: The epithelial-mesenchymal transition (EMT) is emerging as a critical factor for the progression and metastasis of carcinomas, as well as drug resistance. The T-box transcription factor Brachyury has been recently characterized as a driver of EMT in human carcinoma cells. The purpose of this study was to characterize Brachyury as a potential target for lung cancer therapy. Experimental Design: The expression of Brachyury was evaluated by PCR and by immunohistochemistry in human lung tumors and adult normal tissues. Brachyury gene copy number and promoter methylation status were analyzed in tumor tissues with various levels of Brachyury expression. Lung carcinoma cells' susceptibility to T-cell lysis and EGF receptor (EGFR) kinase inhibition were also evaluated relative to the levels of Brachyury. Results: Our results showed Brachyury protein expression in 41% of primary lung carcinomas, including 48% of adenocarcinomas and 25% of squamous cell carcinomas. With the exception of normal testis and some thyroid tissues, the majority of normal tissues evaluated in this study were negative for the expression of Brachyury protein. Brachyury-specific T cells could lyse Brachyury-positive tumors and the level of Brachyury corresponded to resistance of tumor cells to EGFR kinase inhibition. Conclusion: We hypothesize that the elimination of Brachyury-positive tumor cells may be able to prevent and/or diminish tumor dissemination and the establishment of metastases. The ability of Brachyury-specific T-cell lines to lyse Brachyury-positive tumor cells, in vitro, supports the development of Brachyury-based immunotherapeutic approaches for the treatment of lung cancer. ©2012 AACR.


Palmirotta R.,Laboratory of Molecular Diagnostics | De Marchis M.L.,Laboratory of Molecular Diagnostics | Ludovici G.,Laboratory of Molecular Diagnostics | Leone B.,Laboratory of Molecular Diagnostics | And 8 more authors.
International Journal of Biological Markers | Year: 2012

Multicenter studies and biobanking projects require blood transportation from the participating center to a central collection or diagnostic laboratory. The impact of time delays between venous blood collection and peripheral blood mononuclear cells (PBMC) isolation prior to RNA extraction may affect the quality and quantity of isolated nucleic acids for genomic applications. Thus, standard operating procedure (SOP) optimization for the treatment of biological samples before RNA extraction is crucial in a biological repository. In order to define SOPs for whole blood preservation prior to RNA extraction, we sought to determine whether different blood storage times (0, 3, 6, 10, 24, and 30 hours) prior to PBMCs isolation and storage at -80°C, could affect the quality and quantity of extracted RNA. After spectrophotometric quantification, the quality and integrity of RNA were assessed by agarose gel electrophoresis, RNA integrity number and real time-PCR (RT-PCR). Across the different time points we did not observe significant differences within the first 24 hours of blood storage at room temperature, while a significant loss in RNA yield and integrity was detected between 24 and 30 hours. We conclude that time delays before PBMCs isolation prior to RNA extraction may have a significant impact on downstream molecular biological applications. © 2012 Wichtig Editore.


Palmirotta R.,Laboratory of Molecular Diagnostics | De Marchis M.L.,Laboratory of Molecular Diagnostics | Ludovici G.,Laboratory of Molecular Diagnostics | Leone B.,Laboratory of Molecular Diagnostics | And 6 more authors.
Human Mutation | Year: 2012

Familial adenomatous polyposis (FAP) is an autosomal-dominant conditionmainly due to amutation of the adenomatous polyposis coli (APC) gene. The present study reports evidence of a technical issue occurring during the mutational analysis of APC exon 4. Genetic conventional direct sequence analysis of a repetitive AT-rich region in the splice acceptor site of APC intron 3 could be misinterpreted as a pathogenetic frameshift result. However, this potential bias may be bypassed adopting a method for random mutagenesis of DNA based on the use of a triphosphate nucleoside analogues mixture. Using this method as a second-level analysis, we also demonstrated the nonpathogenic nature of the variant in the poly A trait in APC exon 4 region (c.423-4delA) that do not result in aberrant splicing of APC exons 3-4; conversely, we did not find a previously reported T deletion/insertion polymorphism. © 2012 Wiley Periodicals, Inc.


Riondino S.,Laboratory of Thrombosis and Haemostasis | Martini F.,Laboratory of Thrombosis and Haemostasis | La Farina F.,Laboratory of Thrombosis and Haemostasis | Spila A.,InterInstitutional Multidisciplinary Biobank BioBIM | And 2 more authors.
Clinical Biochemistry | Year: 2010

Objectives: To investigate whether sCD40L dosage might represent a useful tool to explore in vivo platelet function. Design and methods: sCD40L and sP-selectin levels and light transmission aggregometry (LTA) were analyzed in 69 healthy donors. Immunoassays were performed on platelet-depleted citrate plasma samples. The effects of in vitro aspirin treatment on the release of sCD40L were investigated in 15 subjects following platelet stimulation. The effects of a 1-month therapeutic course of low-dose aspirin on sP-selectin and sCD40L levels were also investigated. Results: A significant correlation was observed between sCD40L and sP-selectin (p<0.01). In vitro aspirin treatment remarkably decreased sCD40L levels following platelet activation by exogenous agonists. sCD40L directly correlated with LTA (Rho = 0.62, p<0.0001). In vivo aspirin treatment significantly reduced both sP-selectin and sCD40L levels (both p<0.01) in a direct correlation (Rho = 0.66, p<0.05). Conclusions: Citrated plasma samples reflect sCD40L released from platelets, thus yielding the most valid estimates of in vivo circulating levels of this platelet activation markers. © 2010 The Canadian Society of Clinical Chemists.


Sardella G.,University of Rome La Sapienza | Calcagno S.,University of Rome La Sapienza | Mancone M.,University of Rome La Sapienza | Palmirotta R.,Interinstitutional Multidisciplinary BioBank BioBIM | And 9 more authors.
Circulation: Cardiovascular Interventions | Year: 2012

Background: High on-treatment platelet reactivity (HTPR) is associated with adverse outcomes. We aim to compare the novel thienopyridine prasugrel versus double-dose clopidogrel in patients with HTPR and explore the interaction between CYP2C19 genotype and both drugs. Methods and Results: Consecutive stable patients undergoing percutaneous coronary intervention were screened with the Multiplate Analyzer P2-12 assay, defning HTPR as area under the curve >450. Those with HTPR were randomized to prasugrel (10 mg/day) or high-dose clopidogrel (150 mg/day) for 2 weeks and then crossed-over to, respectively, clopidogrel and prasugrel, repeating the P2-12 assay at the end of each cycle. Clinical follow-up (until 3 months) and CYP2C19 genotyping was performed in all patients. The primary end point was platelet reactivity after 14 days of prasugrel versus high-dose clopidogrel. Thirty-two patients were randomized to prasugrel and then high-dose clopidogrel or to high-dose clopidogrel followed by prasugrel. Prasugrel was associated with a significantly lower platelet reactivity than high-dose clopidogrel was (325.8 versus 478.5 area under the curve, P=0.028). No patient treated with prasugrel exhibited HTPR, whereas 9 (28.1%) receiving high-dose clopidogrel still had prevalence of HTPR (P=0.001). Similar findings were obtained changing cutoffs or considering platelet reactivity as a continuous variable. Genotyping showed the same efficacy between high-dose clopidogrel and prasugrel in the 18 (56.3%) CYP2C19 *2 noncarriers (HTPR in 12.5% versus 0, P=0.274), whereas it was significantly worse in the 14 (43.7%) carriers (HTPR in 43.7% versus 0, P=0.003). Conclusions: HTPR is successfully abolished by therapy with prasugrel irrespective of CYP2C19 genotype. Conversely, high-dose clopidogrel can address HTPR only in CYP2C19*2 noncarriers. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01465828. © 2012 American Heart Association, Inc.


Riondino S.,Laboratory of Thrombosis and Haemostasis | La Farina F.,Laboratory of Thrombosis and Haemostasis | Martini F.,Laboratory of Thrombosis and Haemostasis | Guadagni F.,InterInstitutional Multidisciplinary Biobank BioBIM | Ferroni P.,Laboratory of Thrombosis and Haemostasis
International Archives of Occupational and Environmental Health | Year: 2011

Purpose Progressive functional impairments develop with chronic repetitive tasks possibly involving inflammatory mediators. Aim of this study was to analyze systemic inflammatory changes in relation to the possible occurrence of pain and/or disability in video terminal operators (VTOs) undergoing upper-extremity repetitive stress due to chronic overuse. Methods Pain assessments, classification, and grade of impairment relied on self-report questionnaires administered to 21 VTOs and to 21 matched controls. The inflammatory status of the enrolled subjects was analyzed by determination of serum high sensitive C-reactive protein (hs-CRP) as well as systemic levels or monocyte expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Results Serum levels of both cytokines were increased in VTOs compared to controls (P = 0.005 for TNF-α and P = 0.004 for IL-6). TNF-α levels correlated to IL-6 (P = 0.019), which, in turn, was associated to increased hs-CRP (P = 0.012). DASH score allowed to categorize VTOs according to disability. VTOs with mild (DASH = 22) or moderate (DASH = 46) disability (n = 10) had higher serum hs-CRP (P = 0.001) and IL-6 (P = 0.035) levels than VTOs without disabilities (DASH < 17) (n - 11). Monocyte stimulatory TNF-α expression was increased in individuals with mild/moderate disability. Monocyte expression of TNF-α was independently associated to that of IL-6, which, in turn, was associated to increased systemic hs-CRP levels together with mild/moderate functional impairment and weekly commitment to the display screen. Conclusions The results here reported indicate the occurrence of a low-grade inflammatory condition in VTOs with mild/moderate disability, which might allow the early recognition of arising musculoskeletal disorders induced by repetitive stress. © Springer-Verlag 2010.


PubMed | University of Rome Tor Vergata, U.S. National Institutes of Health and Interinstitutional Multidisciplinary Biobank BioBIM
Type: Journal Article | Journal: Oncoimmunology | Year: 2013

Several lines of investigation have revealed the apparent interplay between the immune system of the host and many conventional, standard-of-care anticancer therapies, including chemotherapy and small molecule targeted therapeutics. In particular, preclinical and clinical studies have demonstrated the important role of regulatory T cells (Tregs) in inhibiting immune responses elicited by immunotherapeutic regimens such as those based on anticancer vaccines or checkpoint inhibitors. However, how the number and immunosuppressive function of Tregs change in cancer patients undergoing treatment with non-immune anticancer therapies remains to be precisely elucidated. To determine whether immunostimulatory therapies can be employed successfully in combination with conventional anticancer regimens, we have investigated both the number and function of Tregs obtained from the peripheral blood of carcinoma patients before the initiation and during the course of chemotherapeutic and targeted agent regimens. Our studies show that the treatment of breast cancer patients with tamoxifen plus leuprolide, a gonadotropin releasing hormone agonist, has minimal effects on Tregs, while sunitinib appears to exert differential effects on Tregs among patients with metastatic renal carcinoma. However, the administration of docetaxel to patients with metastatic prostate or breast cancer, as well as that of cisplatin plus vinorelbine to non-small cell lung cancer patients, appears to significantly increase the ratio between effector T cells and Tregs and to reduce the immunosuppressive activity of the latter in the majority of patients. These studies provide the rationale for the selective use of active immunotherapy regimens in combination with specific standard-of-care therapies to achieve the most beneficial clinical outcome among carcinoma patients.

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