Publications by authors named "Salvatore Sciacchitano"

41 Publications

H-Ras gene takes part to the host immune response to COVID-19.

Cell Death Discov 2021 Jun 25;7(1):158. Epub 2021 Jun 25.

Medical Oncology Sant'Andrea Hospital, University La Sapienza, via di Grottarossa 1035-1039, 00189, Rome, Italy.

Ras gene family members play a relevant role in cancer, especially when they are mutated. However, they may play additional roles in other conditions beside cancer. We performed gene expression analysis using the NanoString PanCancer IO 360 panel in the peripheral blood mononuclear cell (PBMC) of six COVID-19 patients and we found that H-Ras gene was significantly upregulated, while both K-Ras and N-Ras genes were downregulated. In particular, H-Ras gene upregulation was more evident in COVID-19 patients with a more severe disease. We compared our results with those obtained by analyzing two different and independent datasets, including a total of 53 COVID-19 patients, in which the gene expression analysis was performed using the Immunology_V2 panel. Comparative analysis of the H-Ras gene expression in these patients confirmed our preliminary results. In both of them, in fact, we were able to confirm the upregulation of the expression of the H-Ras gene. The exact role of this specific upregulation of the H-Ras gene in response to SARS-CoV-2 infection and its possible role in cancer still remains to be elucidated. In conclusion, H-Ras gene participates to the host immune response to SARS-CoV-2 virus infection, especially in patients affected by the most severe form of the COVID-19.
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http://dx.doi.org/10.1038/s41420-021-00541-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256395PMC
June 2021

Generation and characterization of the human induced pluripotent stem cell (hiPSC) line NCUFi001-A from a patient carrying KCNQ1 G314S mutation.

Stem Cell Res 2021 Jul 5;54:102418. Epub 2021 Jun 5.

Laboratory of Biomedical Research, Niccolò Cusano University Foundation, Via Don Carlo Gnocchi 3, 00166 Rome, Italy; Medical Genetics Unit, Tor Vergata University Hospital, PTV, Viale Montpellier 1, 00133 Rome, Italy.

In this study we describe the generation and characterization of an human induced pluripotent stem cell (hiPSC) line from a long QT syndrome type 1 (LQT1) patient carrying the KCNQ1 c.940 G > A (p.Gly314Ser) mutation. This patient-specific iPSC line has been obtained by using non-integrational Sendai reprogramming method, expresses pluripotency markers and has the capacity to differentiate into the three germ layers and into spontaneously beating cardiomyocytes (iPSC-CMs).
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http://dx.doi.org/10.1016/j.scr.2021.102418DOI Listing
July 2021

Interleukin‑6 signalling as a valuable cornerstone for molecular medicine (Review).

Int J Mol Med 2021 Jun 28;47(6). Epub 2021 Apr 28.

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Policlinico Universitario, I‑98125 Messina, Italy.

The biological abilities of interleukin‑6 (IL‑6) have been under investigation for nearly 40 years. IL‑6 works through an interaction with the complex peptide IL‑6 receptor (IL‑6R). IL‑6 is built with four α‑chain nanostructures, while two different chains, IL‑6Rα (gp80) and gp130/IL6β (gp130), are included in IL‑6R. The three‑dimensional shapes of the six chains composing the IL‑6/IL‑6R complex are the basis for the nanomolecular roles of IL‑6 signalling. Genes, pseudogenes and competitive endogenous RNAs of IL‑6 have been identified. In the present review, the roles played by miRNA in the post‑transcriptional regulation of IL‑6 expression are evaluated. mRNAs are absorbed via the 'sponge' effect to dynamically balance mRNA levels and this has been assessed with regard to IL‑6 transcription efficiency. According to current knowledge on molecular and nanomolecular structures involved in active IL‑6 signalling, two different IL‑6 models have been proposed. IL‑6 mainly has functions in inflammatory processes, as well as in cognitive activities. Furthermore, the abnormal production of IL‑6 has been found in patients with severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2; also known as COVID‑19). In the present review, both inflammatory and cognitive IL‑6 models were analysed by evaluating the cytological and histological locations of IL‑6 signalling. The goal of this review was to illustrate the roles of the classic and trans‑signalling IL‑6 pathways in endocrine glands such as the thyroid and in the central nervous system. Specifically, autoimmune thyroid diseases, disorders of cognitive processes and SARS‑CoV‑2 virus infection have been examined to determine the contribution of IL‑6 to these disease states.
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http://dx.doi.org/10.3892/ijmm.2021.4940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057292PMC
June 2021

Gene signature and immune cell profiling by high-dimensional, single-cell analysis in COVID-19 patients, presenting Low T3 syndrome and coexistent hematological malignancies.

J Transl Med 2021 04 1;19(1):139. Epub 2021 Apr 1.

Department of Clinical and Molecular Medicine, Sapienza University, Via di Grottarossa, 1035/1039, 00189, Rome, Italy.

Background: Low T3 syndrome is frequent in patients admitted to intensive care units for critical illness and pneumonia. It has been reported also in patients with COVID-19, Hodgkin disease and chronic lymphocytic leukemia. We analyzed the clinical relevance of Low T3 syndrome in COVID-19 patients and, in particular, in those with associated hematological malignancies.

Methods: Sixty-two consecutive patients, hospitalized during the first wave of SARS-CoV-2 outbreak in Sant'Andrea University Hospital in Rome, were subdivided in 38 patients (Group A), showing low levels of FT3, and in 24 patients (Group B), with normal FT3 serum values. During the acute phase of the disease, we measured serum, radiologic and clinical disease severity markers and scores, in search of possible correlations with FT3 serum values. In addition, in 6 COVID-19 patients, 4 with Low T3 syndrome, including 2 with a hematological malignancy, and 2 with normal FT3 values, we performed, high-dimensional single-cell analysis by mass cytometry, multiplex cytokine assay and gene expression profiling in peripheral blood mononuclear cells (PBMC).

Results: Low FT3 serum values were correlated with increased Absolute Neutrophil Count, NLR and dNLR ratios and with reduced total count of CD3+, CD4+ and CD8+ T cells. Low FT3 values correlated also with increased levels of inflammation, tissue damage and coagulation serum markers as well as with SOFA, LIPI and TSS scores. The CyTOF analysis demonstrated reduction of the effector memory and terminal effector subtypes of the CD4+ T lymphocytes. Multiplex cytokine assay indicates that mainly IL-6, IP-10 and MCAF changes are associated with FT3 serum levels, particularly in patients with coexistent hematological malignancies. Gene expression analysis using Nanostring identified four genes differently expressed involved in host immune response, namely CD38, CD79B, IFIT3 and NLRP3.

Conclusions: Our study demonstrates that low FT3 serum levels are associated with severe COVID-19. Our multi-omics approach suggests that T3 is involved in the immune response in COVID-19 and coexistent hematological malignancy and new possible T3 target genes in these patients have been identified.
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http://dx.doi.org/10.1186/s12967-021-02805-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016508PMC
April 2021

Transparency in Negotiation of European Union With Big Pharma on COVID-19 Vaccines.

Front Public Health 2021;9:647955. Epub 2021 Feb 18.

Laboratory of Surgical and Experimental Pathology, St Andrea University Hospital, Rome, Italy.

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http://dx.doi.org/10.3389/fpubh.2021.647955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930234PMC
March 2021

Circulating Vitamin D levels status and clinical prognostic indices in COVID-19 patients.

Respir Res 2021 Mar 3;22(1):76. Epub 2021 Mar 3.

Respiratory Unit, Sant'Andrea Hospital, Sapienza University of Rome, Via di grottarossa, 1035, Rome, Italy.

Background: Several immune mechanisms activate in COVID-19 pathogenesis. Usually, coronavirus infection is characterized by dysregulated host immune responses, interleukine-6 increase, hyper-activation of cytotoxic CD8 T lymphocytes. Interestingly, Vitamin D deficiency has been often associated with altered immune responses and infections. In the present study, we evaluated Vitamin D plasma levels in patients affected with different lung involvement during COVID-19 infection.

Methods: Lymphocyte phenotypes were assessed by flow cytometry. Thoracic CT scan involvement was obtained by an image analysis program.

Results: Vitamin D levels were deficient in (80%) of patients, insufficient in (6.5%) and normal in (13.5%). Patients with very low Vitamin D plasma levels had more elevated D-Dimer values, a more elevated B lymphocyte cell count, a reduction of CD8 + T lymphocytes with a low CD4/CD8 ratio, more compromised clinical findings (measured by LIPI and SOFA scores) and thoracic CT scan involvement.

Conclusions: Vitamin D deficiency is associated with compromised inflammatory responses and higher pulmonary involvement in COVID-19 affected patients. Vitamin D assessment, during COVID-19 infection, could be a useful analysis for possible therapeutic interventions.

Trial Registration: 'retrospectively registered'.
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http://dx.doi.org/10.1186/s12931-021-01666-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928197PMC
March 2021

Scientific leadership: the Italian Government's perspective.

Lancet 2019 08;394(10198):562-563

Italian Ministry of Health, Lungotevere Ripa, 1-00153 Rome, Italy.

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http://dx.doi.org/10.1016/S0140-6736(19)30496-9DOI Listing
August 2019

Nanostructures: between natural environment and medical practice.

Rev Environ Health 2018 Sep;33(3):295-307

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Policlinico Universitario, Consolare Valeria 1, Messina, Italy.

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http://dx.doi.org/10.1515/reveh-2017-0036DOI Listing
September 2018

Galectin-3: The Impact on the Clinical Management of Patients with Thyroid Nodules and Future Perspectives.

Int J Mol Sci 2018 Feb 2;19(2). Epub 2018 Feb 2.

Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675 München, Germany.

Galectins (S-type lectins) are an evolutionarily-conserved family of lectin molecules, which can be expressed intracellularly and in the extracellular matrix, as well. Galectins bind β-galactose-containing glycoconjugates and are functionally active in converting glycan-related information into cell biological programs. Altered glycosylation notably occurring in cancer cells and expression of specific galectins provide, indeed, a fashionable mechanism of molecular interactions able to regulate several tumor relevant functions, among which are cell adhesion and migration, cell differentiation, gene transcription and RNA splicing, cell cycle and apoptosis. Furthermore, several galectin molecules also play a role in regulating the immune response. These functions are strongly dependent on the cell context, in which specific galectins and related glyco-ligands are expressed. Thyroid cancer likely represents the paradigmatic tumor model in which experimental studies on galectins' glycobiology, in particular on galectin-3 expression and function, contributed greatly to the improvement of cancer diagnosis. The discovery of a restricted expression of galectin-3 in well-differentiated thyroid carcinomas (WDTC), compared to normal and benign thyroid conditions, contributed also to promoting preclinical studies aimed at exploring new strategies for imaging thyroid cancer in vivo based on galectin-3 immuno-targeting. Results derived from these recent experimental studies promise a further improvement of both thyroid cancer diagnosis and therapy in the near future. In this review, the biological role of galectin-3 expression in thyroid cancer, the validation and translation to a clinical setting of a galectin-3 test method for the preoperative characterization of thyroid nodules and a galectin-3-based immuno-positron emission tomography (immuno-PET) imaging of thyroid cancer in vivo are presented and discussed.
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http://dx.doi.org/10.3390/ijms19020445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855667PMC
February 2018

Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z.

Int J Mol Sci 2018 Jan 26;19(2). Epub 2018 Jan 26.

Department of Clinical and Molecular Medicine, Sapienza University, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy.

Galectin-3 (Gal-3) regulates basic cellular functions such as cell-cell and cell-matrix interactions, growth, proliferation, differentiation, and inflammation. It is not surprising, therefore, that this protein is involved in the pathogenesis of many relevant human diseases, including cancer, fibrosis, chronic inflammation and scarring affecting many different tissues. The papers published in the literature have progressively increased in number during the last decades, testifying the great interest given to this protein by numerous researchers involved in many different clinical contexts. Considering the crucial role exerted by Gal-3 in many different clinical conditions, Gal-3 is emerging as a new diagnostic, prognostic biomarker and as a new promising therapeutic target. The current review aims to extensively examine the studies published so far on the role of Gal-3 in all the clinical conditions and diseases, listed in alphabetical order, where it was analyzed.
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http://dx.doi.org/10.3390/ijms19020379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855601PMC
January 2018

Comparative analysis of diagnostic performance, feasibility and cost of different test-methods for thyroid nodules with indeterminate cytology.

Oncotarget 2017 Jul;8(30):49421-49442

Laboratory of Surgical and Experimental Pathology, St Andrea University Hospital, 00189 Rome, Italy.

Since it is impossible to recognize malignancy at fine needle aspiration (FNA) cytology in indeterminate thyroid nodules, surgery is recommended for all of them. However, cancer rate at final histology is <30%. Many different test-methods have been proposed to increase diagnostic accuracy in such lesions, including Galectin-3-ICC (GAL-3-ICC), BRAF mutation analysis (BRAF), Gene Expression Classifier (GEC) alone and GEC+BRAF, mutation/fusion (M/F) panel, alone, M/F panel+miRNA GEC, and M/F panel by next generation sequencing (NGS), FDG-PET/CT, MIBI-Scan and TSHR mRNA blood assay.We performed systematic reviews and meta-analyses to compare their features, feasibility, diagnostic performance and cost. GEC, GEC+BRAF, M/F panel+miRNA GEC and M/F panel by NGS were the best in ruling-out malignancy (sensitivity = 90%, 89%, 89% and 90% respectively). BRAF and M/F panel alone and by NGS were the best in ruling-in malignancy (specificity = 100%, 93% and 93%). The M/F by NGS showed the highest accuracy (92%) and BRAF the highest diagnostic odds ratio (DOR) (247). GAL-3-ICC performed well as rule-out (sensitivity = 83%) and rule-in test (specificity = 85%), with good accuracy (84%) and high DOR (27) and is one of the cheapest (113 USD) and easiest one to be performed in different clinical settings.In conclusion, the more accurate molecular-based test-methods are still expensive and restricted to few, highly specialized and centralized laboratories. GAL-3-ICC, although limited by some false negatives, represents the most suitable screening test-method to be applied on a large-scale basis in the diagnostic algorithm of indeterminate thyroid lesions.
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http://dx.doi.org/10.18632/oncotarget.17220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564779PMC
July 2017

Antiproliferative Effects of 1α-OH-vitD in Malignant Melanoma: Potential Therapeutic implications.

Sci Rep 2017 01 11;7:40370. Epub 2017 Jan 11.

Pathology Research Laboratory, Sant'Andrea University Hospital, via di Grottarossa 1035, 00189 Rome, Italy.

Early detection and surgery represent the mainstay of treatment for superficial melanoma, but for high risk lesions (Breslow's thickness >0.75 mm) an effective adjuvant therapy is lacking. Vitamin D insufficiency plays a relevant role in cancer biology. The biological effects of 1α hydroxycholecalciferol on experimental melanoma models were investigated. 105 melanoma patients were checked for 25-hydroxycholecalciferol (circulating vitamin D) serum levels. Human derived melanoma cell lines and in vivo xenografts were used for studying 1α-hydroxycholecalciferol-mediated biological effects on cell proliferation and tumor growth. 99 out of 105 (94%) melanoma patients had insufficient 25-hydroxycholecalciferol serum levels. Interestingly among the six with vitamin D in the normal range, five had a diagnosis of in situ/microinvasive melanoma. Treatment with 1α-hydroxycholecalciferol induced antiproliferative effects on melanoma cells in vitro and in vivo, modulating the expression of cell cycle key regulatory molecules. Cell cycle arrest in G1 or G2 phase was invariably observed in vitamin D treated melanoma cells. The antiproliferative activity induced by 1α-hydroxycholecalciferol in experimental melanoma models, together with the discovery of insufficient 25-hydroxycholecalciferol serum levels in melanoma patients, provide the rationale for using vitamin D in melanoma adjuvant therapy, alone or in association with other therapeutic options.
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http://dx.doi.org/10.1038/srep40370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225467PMC
January 2017

Combined clinical and ultrasound follow-up assists in malignancy detection in Galectin-3 negative Thy-3 thyroid nodules.

Endocrine 2016 Oct 16;54(1):139-147. Epub 2015 Oct 16.

Laboratory of Surgical and Experimental Pathology, St Andrea University Hospital, Via di Grottarossa, 1035/39, 00189, Rome, Italy.

The use of galectin-3 ThyroTest in the preoperative evaluation of cytologically indeterminate (Thy-3) thyroid nodules has been largely validated by retrospective and prospective multicentre studies. Here we report the results of galectin-3 ThyroTest routinely applied in the management of Thy-3 nodules in combination with clinical and ultrasonography (US) examination, in which galectin-3 positive nodules were directly referred to surgery whereas galectin-3 negative lesions were considered for clinical and US long-term follow-up. A cohort of 331 patients, bearing 340 thyroid Thy-3 nodules, was enrolled and subjected to galectin-3 expression analysis. A total of 256 galectin-3 negative nodules were directed to periodical clinical and US examination, while 84 galectin-3 positive cases were referred to surgery. Excluding 63 dropout patients plus 15 patients that were operated because of clinical reasons the remaining 176 galectin-3 negative nodules were followed with clinical and US examination for an average period of 31 months. During the follow-up, the volume of galectin-3 negative nodules was unchanged in 85 cases (48 %), reduced in 47 (27 %), and increased in 44 (25 %). Based on combined clinical features and US follow-up results, a total of 36 out of 191 galectin-3 negative nodules (19 %) were referred to surgery, with a final histological finding of 28 benign lesions, three follicular tumor of uncertain malignant potential (FT-UMP), and five malignant lesions, corresponding to a 7 % false negative rate. In the group of 84 galectin-3 positive nodules, we detected 65 thyroid cancers with a prevalence of 77 %, 12 FT-UMPs, and 7 false positive lesions, corresponding to a 4 % false positive rate. A total of 150 patients were not operated and are still under clinical and US monitoring while surgery was performed in 118 patients with a final 70 thyroid cancers diagnosed, corresponding to a 59 % prevalence of malignancy detected at surgery and to a 26 % prevalence of malignancy among the entire Thy-3 nodule population. Galectin-3 ThyroTest is an easy and cheap diagnostic procedure that integrates conventional fine-needle-aspiration cytology, reduces the number of unnecessary thyroidectomies and increases the rate of malignancy at surgery. Clinical and US follow-up of galectin-3 negative lesions allows to further reduce false negative cases.
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http://dx.doi.org/10.1007/s12020-015-0774-8DOI Listing
October 2016

Detection of ATM germline variants by the p53 mitotic centrosomal localization test in BRCA1/2-negative patients with early-onset breast cancer.

J Exp Clin Cancer Res 2016 09 6;35(1):135. Epub 2016 Sep 6.

Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute - IRCCS, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: Variant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Costs and time of sequencing and ATM variant complexity make large-scale, general population screenings not cost-effective yet. Recently, we developed a straightforward, rapid, and inexpensive test based on p53 mitotic centrosomal localization (p53-MCL) in peripheral blood mononuclear cells (PBMCs) that diagnoses mutant ATM zygosity and recognizes tumor-associated ATM polymorphisms.

Methods: Fresh PBMCs from 496 cancer patients were analyzed by p53-MCL: 90 cases with familial BRCA1/2-positive and -negative breast and/or ovarian cancer, 337 with sporadic cancers (ovarian, lung, colon, and post-menopausal breast cancers), and 69 with breast/thyroid cancer. Variants were confirmed by ATM sequencing.

Results: A total of seven individuals with ATM variants were identified, 5/65 (7.7 %) in breast cancer cases of familial breast and/or ovarian cancer and 2/69 (2.9 %) in breast/thyroid cancer. No variant ATM carriers were found among the other cancer cases. Excluding a single case in which both BRCA1 and ATM were mutated, no p53-MCL alterations were observed in BRCA1/2-positive cases.

Conclusions: These data validate p53-MCL as reliable and specific test for germline ATM variants, confirm ATM as breast cancer susceptibility gene, and highlight a possible association with breast/thyroid cancers.
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http://dx.doi.org/10.1186/s13046-016-0410-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012020PMC
September 2016

Safety and efficacy of denosumab in osteoporotic hemodialysed patients.

J Nephrol 2017 Apr 9;30(2):271-279. Epub 2016 Jul 9.

Nephrology and Dialysis Unit, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy.

Background And Aims: In elderly subjects, renal insufficiency and osteoporosis often coexist with high risk of fracture and elevated socio-economic burden. Today a large number of effective anti-osteoporotic drugs are available but generally they are contraindicated in patients with chronic kidney disease (CKD) because of their progressive accumulation. Denosumab, instead, does not require dose adjustments for different degrees of renal impairment so it can be a valid treatment in osteoporotic patients with CKD. Limited data are available in the literature concerning the use of denosumab in hemodialysis (HD). The aim of our study was, therefore, to study the efficacy and tolerability of this drug in this particular subset of patients.

Methods: We retrospectively reviewed the charts of 12 osteoporotic HD patients who received a single 60-mg subcutaneous dose of denosumab every 6 months for an observation period of 24 months. Serum electrolyte, markers of bone turnover and quantitative ultrasound (QUS) were evaluated.

Results: Over 24 months, we observed a gradual improvement of bone metabolism: β-CrossLaps from 2567.08 ± 1264 to 1492.5 ± 1182.5 pg/ml; bone alkaline phosphatase (BALP) from 33.5 ± 28.8 to 11.8 ± 3.7 mcg/l, and of QUS index (T-score from -5.33 ± 1.58 to -4.84 ± 1.2; risk of fracture from 13.9 ± 4.7 to 11.07 ± 5.3 %). Few cases of hypocalcemia were detected, more significant after the first and second injection, but with careful monitoring of serum calcium and rapid therapy adjustment we could easily manage serum Ca levels.

Conclusions: Our pilot experience highlights the safety and efficacy of denosumab in the treatment of osteoporosis in HD patients, potentially supporting its use to reduce the burden of fractures in this patient population.
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http://dx.doi.org/10.1007/s40620-016-0334-1DOI Listing
April 2017

Investigation of VOCs associated with different characteristics of breast cancer cells.

Sci Rep 2015 Aug 25;5:13246. Epub 2015 Aug 25.

Department of Electronic Engineering, University of Rome Tor Vergata, Via del Politecnico 1, 00133 Rome, Italy.

The efficacy of breath volatile organic compounds (VOCs) analysis for the screening of patients bearing breast cancer lesions has been demonstrated by using gas chromatography and artificial olfactory systems. On the other hand, in-vitro studies suggest that VOCs detection could also give important indications regarding molecular and tumorigenic characteristics of tumor cells. Aim of this study was to analyze VOCs in the headspace of breast cancer cell lines in order to ascertain the potentiality of VOCs signatures in giving information about these cells and set-up a new sensor system able to detect breast tumor-associated VOCs. We identified by Gas Chromatography-Mass Spectrometry analysis a VOCs signature that discriminates breast cancer cells for: i) transformed condition; ii) cell doubling time (CDT); iii) Estrogen and Progesterone Receptors (ER, PgR) expression, and HER2 overexpression. Moreover, the signals obtained from a temperature modulated metal oxide semiconductor gas sensor can be classified in order to recognize VOCs signatures associated with breast cancer cells, CDT and ER expression. Our results demonstrate that VOCs analysis could give clinically relevant information about proliferative and molecular features of breast cancer cells and pose the basis for the optimization of a low-cost diagnostic device to be used for tumors characterization.
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http://dx.doi.org/10.1038/srep13246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548242PMC
August 2015

Homeodomain-interacting protein kinase2 in human idiopathic pulmonary fibrosis.

J Cell Physiol 2013 Jan;228(1):235-41

Università di Roma La Sapienza, Ospedale Sant'Andrea, Dipartimento di Medicina Clinica e Molecolare, Roma, Italy.

Homeodomain-interacting protein kinase 2 (Hipk2) is an emerging player in cell response to genotoxic agents that contributes to the cell's decision between cell cycle arrest or apoptosis. HIPK2 acts as co-regulator of an increasing number of transcription factors and modulates many different basic cellular processes such as apoptosis, proliferation, DNA damage response, differentiation. Idiopathic pulmonary fibrosis (IPF) is characterized by an anatomical disarrangement of the lung due to fibroblast proliferation, extracellular matrix deposition and lung function impairment. Although the role of inflammation is still debated, attention has been focused on lung cell functions as fibroblast phenotype and activity. Aim of the present study was to analyze the loss of heterozygosity (LOH) at HIPK2 locus 7q32.34 in human lung fibroblasts and the HIPK2 expression in 15 IPF samples and in four primary fibroblast cell cultures isolated from IPF biopsies using semi-quantitative RT-PCR, Western blots and immunohistochemistry. We demonstrated a frequency of LOH in IPF fibroblasts of 46% for the internal D7S6440 microsatellite and 26.6% for the external D7S2468 microsatellite. Furthermore, we demonstrated low HIPK2 protein expression in those fibroblasts from IPF patients that present the HIPK2 LOH. The restoration of HIPK2 expression in IPF derived cells induced a significant reduction of chemoresistance after treatment with cisplatin. The results obtained allow us to hypothesize that HIPK2 dysfunction may play a role in fibroblasts behavior and in IPF pathogenesis. HIPK2 may be considered as a novel potential target for anti-fibrosis therapy.
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http://dx.doi.org/10.1002/jcp.24129DOI Listing
January 2013

The loss of the p53 activator HIPK2 is responsible for galectin-3 overexpression in well differentiated thyroid carcinomas.

PLoS One 2011 17;6(6):e20665. Epub 2011 Jun 17.

Research Center, St. Pietro Fatebenefratelli Hospital, Rome, Italy.

Background: Galectin-3 (Gal-3) is an anti-apoptotic molecule involved in thyroid cells transformation. It is specifically overexpressed in thyroid tumour cells and is currently used as a preoperative diagnostic marker of thyroid malignancy. Gal-3 expression is downregulated by wt-p53 at the transcriptional level. In well-differentiated thyroid carcinomas (WDTCs) there is an unexplained paradoxical concomitant expression of Gal-3 and wt-p53. HIPK2 is a co-regulator of different transcription factors, and modulates basic cellular processes mainly through the activation of wt-p53. Since we demonstrated that HIPK2 is involved in p53-mediated Gal-3 downregulation, we asked whether HIPK2 deficiency might be responsible for such paradoxical Gal-3 overexpression in WDTC.

Methodology/principal Findings: We analyzed HIPK2 protein and mRNA levels, as well as loss of heterozygosity (LOH) at the HIPK2 locus (7q32-34), in thyroid tissue samples. HIPK2 protein levels were high in all follicular hyperplasias (FHs) analyzed. Conversely, HIPK2 was undetectable in 91.7% of papillary thyroid carcinomas (PTCs) and in 60.0% of follicular thyroid carcinomas (FTCs). HIPK2 mRNA levels were upregulated in FH compared to normal thyroid tissue (NTT), while PTC showed mean HIPK2 mRNA levels lower than FH and, in 61.5% of cases, also lower than NTT. We found LOH at HIPK-2 gene locus in 37.5% of PTCs, 14.3% of FTCs and 18.2% of follicular adenomas. To causally link these data with Gal-3 upregulation, we performed in vitro experiments, using the PTC-derived K1 cells, in which HIPK2 expression was manipulated by RNA interference (RNAi) or plasmid-mediated overexpression. HIPK2 RNAi was associated with Gal-3 upregulation, while HIPK2 overexpression with Gal-3 downregulation.

Conclusions/significance: Our results indicate that HIPK2 expression and function are impaired in WDTCs, in particular in PTCs, and that this event explains Gal-3 overexpression typically observed in these types of tumours. Therefore, HIPK2 can be considered as a new tumour suppressor gene for thyroid cancers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117790PMC
November 2011

Methodology and technical requirements of the galectin-3 test for the preoperative characterization of thyroid nodules.

Appl Immunohistochem Mol Morphol 2012 Jan;20(1):2-7

Cellular and Molecular Tumor Pathology Laboratory, Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden.

In the last decade, the β-galactosyl binding protein galectin-3 has been the object of extensive molecular, structural, and functional studies aimed to clarify its biological role in cancer. Multicenter studies also contributed to discover the potential clinical value of galectin-3 expression analysis in distinguishing, preoperatively, benign from malignant thyroid nodules. As a consequence galectin-3 is receiving significant attention as tumor marker for thyroid cancer diagnosis, but some conflicting results mostly owing to methodological problems have been published. The possibility to apply preoperatively a reliable galectin-3 test method on fine needle aspiration biopsy (FNA)-derived thyroid cells represents an important achievement. When correctly applied, the method reduces consistently the gray area of thyroid FNA cytology, contributing to avoid unnecessary thyroid surgery. Although the efficacy and reliability of the galectin-3 test method have been extensively proved in several studies, its translation in the clinical setting requires well-standardized reagents and procedures. After a decade of experimental work on galectin-3-related basic and translational research projects, the major methodological problems that may potentially impair the diagnostic performance of galectin-3 immunotargeting are highlighted and discussed in detail. A standardized protocol for a reliable galectin-3 expression analysis is finally provided. The aim of this contribution is to improve the clinical management of patients with thyroid nodules, promoting the preoperative use of a reliable galectin-3 test method as ancillary technique to conventional thyroid FNA cytology. The final goal is to decrease unnecessary thyroid surgery and its related social costs.
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http://dx.doi.org/10.1097/PAI.0b013e31821ee9bbDOI Listing
January 2012

COX-2 is induced by HGF stimulation in Met-positive thyroid papillary carcinoma cells and is involved in tumour invasiveness.

J Pathol 2009 Aug;218(4):487-94

Dipartimento di Medicina Sperimentale, II Facoltà di Medicina e Chirurgia, Ospedale Sant'Andrea, Università La Sapienza, Roma, Italy.

Thyroid papillary carcinoma (TPC) cells express high levels of cytoplasmic cyclo-oxygenase 2 protein. Analysis of microdissected samples of the tumour and of the paired normal thyroid tissue confirmed that mRNA transcripts for cyclo-oxygenase 2 (COX-2) were significantly more numerous in the tumour (7.6 +/- 13-fold; p = 0.01). High levels of COX-2 mRNA were not associated with age, sex, tumour size or lymph node metastasis. COX-2 was not homogeneously expressed throughout the tumour, but was significantly higher at the tumour invasion front. Hepatocyte growth factor (HGF) can up-regulate the expression of COX-2 mRNA. A marked increase in COX-2 mRNA levels was observed in 8/8 primary TPC cultures after HGF stimulation (6.3 +/- 6-fold) and in two papillary carcinoma cell lines (TPC-1 and NPA). Specific involvement of the high-affinity HGF receptor (Met protein) was suggested by the observation that PHA-665752, an inhibitor of the catalytic activity of c-Met kinase, caused a 54% reduction of the hepatocyte growth factor-induced COX-2 up-regulation. The possibility that HGF-Met interactions also had a causative role in the up-regulation of COX-2 in vivo was investigated in 30 tumour samples, where it was found that there was a statistically significant correlation (p = 0.001, r = 0.85) in the levels of expression of MET and COX-2 RNAs. The biological role of COX-2 in TPC cells was investigated by treating the TPC cell lines with the specific COX-2 inhibitor NS-398. It was found that NS-398 treatment significantly reduced the migration (50-75%) and invasiveness (47-92%) of tumour cells, but did not alter cell proliferation. Our data suggest that the increased expression of Met protein in TPC cells has a role in up-regulating the expression of COX-2, which in turn contributes to the invasive capacity of TPC cells.
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http://dx.doi.org/10.1002/path.2556DOI Listing
August 2009

Gal-3 is stimulated by gain-of-function p53 mutations and modulates chemoresistance in anaplastic thyroid carcinomas.

J Pathol 2009 May;218(1):66-75

S. Pietro Fatebenefratelli Hospital, Rome, Italy.

Galectin-3 (Gal-3) is an anti-apoptotic molecule of the beta-galactoside-binding lectin family. Gal-3 is down-regulated by wt-p53 and this repression is required for p53-induced apoptosis. Since poorly differentiated thyroid carcinomas (PDTCs) and anaplastic thyroid carcinomas (ATCs) frequently harbour p53 mutations, we asked whether Gal-3 expression and activity could be influenced by such mutations in these tumours. We found a positive correlation between Gal-3 expression and p53 mutation in human thyroids and in thyroid carcinoma cell lines (TCCLs) harbouring different p53 mutations. Gal-3 was over-expressed in most ATCs and TCCLs, especially those with the most frequently detected p53 mutation (p53(R273H)). Over-expression of p53(R273H) in two p53-null cells (SAOS-2 and SW-1736) as well as in two wt-p53-carrying TCCLs (TPC-1 and K1), stimulated Gal-3 expression, while interference with p53(R273H) endogenous expression in ARO cells down-regulated Gal-3 expression. Conversely, over-expression of wt-p53 in ARO cells restored the inhibitory effect on Gal-3 expression. ARO cells are highly resistant to apoptosis and express both p53 and Gal-3, which are increased upon cisplatin treatment. Interference with Gal-3 expression in these cells stimulated their chemosensitivity. In conclusion, gain-of-function p53 mutant acquires the de novo ability to stimulate Gal-3 expression and to increase chemoresistance in ATCs.
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http://dx.doi.org/10.1002/path.2510DOI Listing
May 2009

Thyroid cancer imaging in vivo by targeting the anti-apoptotic molecule galectin-3.

PLoS One 2008 20;3(11):e3768. Epub 2008 Nov 20.

Cellular and Molecular Tumor Pathology Laboratory, Cancer Center Karolinska, Karolinska Hospital, Stockholm, Sweden.

Background: The prevalence of thyroid nodules increases with age, average 4-7% for the U.S.A. adult population, but it is much higher (19-67%) when sub-clinical nodules are considered. About 90% of these lesions are benign and a reliable approach to their preoperative characterization is necessary. Unfortunately conventional thyroid scintigraphy does not allow the distinction among benign and malignant thyroid proliferations but it provides only functional information (cold or hot nodules). The expression of the anti-apoptotic molecule galectin-3 is restricted to cancer cells and this feature has potential diagnostic and therapeutic implications. We show here the possibility to obtain thyroid cancer imaging in vivo by targeting galectin-3.

Methods: The galectin-3 based thyroid immuno-scintigraphy uses as radiotracer a specific (99m)Tc-radiolabeled mAb. A position-sensitive high-resolution mini-gamma camera was used as imaging capture device. Human galectin-3 positive thyroid cancer xenografts (ARO) and galectin-3 knockout tumors were used as targets in different experiments in vivo. 38 mice with tumor mass of about 1 gm were injected in the tail vein with 100 microCi of (99m)Tc-labeled mAb to galectin-3 (30 microg protein/in 100 microl saline solution). Tumor images were acquired at 1 hr, 3 hrs, 6 hrs, 9 hrs and 24 hrs post injection by using the mini-gamma camera.

Findings: Results from different consecutive experiments show an optimal visualization of thyroid cancer xenografts between 6 and 9 hours from injection of the radiotracer. Galectin-3 negative tumors were not detected at all. At 6 hrs post-injection galectin-3 expressing tumors were correctly visualized, while the whole-body activity had essentially cleared.

Conclusions: These results demonstrate the possibility to distinguish preoperatively benign from malignant thyroid nodules by using a specific galectin-3 radio-immunotargeting. In vivo imaging of thyroid cancer may allow a better selection of patients referred to surgery. The possibility to apply this method for imaging and treatment of other galectin-3 expressing tumors is also discussed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0003768PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2582451PMC
February 2009

Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study.

Lancet Oncol 2008 Jun 19;9(6):543-9. Epub 2008 May 19.

Department of Pathology, St Andrea University Hospital, Rome, Italy.

Background: In the USA, about 30 200 well-differentiated thyroid carcinomas were diagnosed in 2007, but the prevalence of thyroid nodules is much higher (about 5% of the adult population). Unfortunately, the preoperative characterisation of follicular thyroid nodules is still a challenge, and many benign lesions, which remain indeterminate after fine-needle aspiration (FNA) cytology are referred to surgery. About 85% of these thyroid nodules are classified as benign at final histology. We aimed to assess the diagnostic effect of galectin-3 expression analysis in distinguishing preoperatively benign from malignant follicular thyroid nodules when FNA findings were indeterminate.

Methods: 544 patients were enrolled between June 1, 2003, and Aug 30, 2006. We used a purified monoclonal antibody to galectin-3, a biotin-free immunocytohistochemical assay, and a morphological and phenotypic analysis of FNA-derived cell-block preparations. Galectin-3-expression analysis was applied preoperatively on 465 follicular thyroid proliferations that were candidates for surgery, and its diagnostic accuracy was compared with the final histology.

Findings: 31 patients were excluded because they had small galectin-3-negative thyroid nodules; we did not have data for 47 patients; and one patient with an oncocytic nodule was excluded. 331 (71%) of the assessable 465 preoperative thyroid FNA samples did not express galectin-3. 280 (85%) of these galectin-3-negative lesions were classified as benign at final histology. Galectin-3 expression was detected, instead, in 134 of 465 (29%) thyroid proliferations, 101 (75%) of which were confirmed as malignant. The overall sensitivity of the galectin-3 test was 78% (95% CI 74-82) and specificity was 93% (90-95). Estimated positive predictive value was 82% (79-86) and negative predictive value was 91% (88-93). 381 (88%) of 432 patients with follicular thyroid nodules who were referred for thyroidectomy were correctly classified preoperatively by use of the galectin-3 test. However, 29 (22%) of 130 cancers were missed by the galectin-3 method.

Interpretation: Our findings show that if the option of surgery was based theoretically on galectin-3 expression alone, only 134 thyroid operations would have been done in 465 patients; therefore a large proportion (71%) of unnecessary thyroid surgical procedures could be avoided, although a number of galectin-3-negative cancers could be potentially missed. The galectin-3 test proposed here does not replace conventional FNA cytology, but represents a complementary diagnostic method for those follicular nodules that remain indeterminate.
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http://dx.doi.org/10.1016/S1470-2045(08)70132-3DOI Listing
June 2008

Expression of NA/1 symporter (NIS) in endometrial mucosa of fertile, sterile and post-menopausal women.

Histol Histopathol 2008 05;23(5):549-54

Dipartimento di Patologia Umana, Policlinico Universitario, University of Messina, Italy.

The expression of the Na/I Symporter (NIS) in the basolateral cell membrane of the thyroid follicular cells is responsible for the active accumulation of iodide within the thyroid gland and for the subsequent biosynthesis of thyroid hormones. However, several tissues, such as salivary glands, breast, stomach, colon, ovary and endometrium, express NIS even if they are unable to organify iodide. In order to investigate a possible role of NIS in the endometrium, we analyzed, by immunochemistry, the expression of NIS in 44 endometrial samples of 20 patients with primary unexplained infertility, 14 fertile women and 10 in postmenopausal. NIS immunostaining was detected in endometrial cells belonging to the majority of sterile, post-menopausal and fertile women. However, the sterile and post-menopausal patients showed a higher percentage of NIS reactive cells compared to the fertile women (60+/-21% and 57+/-18% vs 19+/-9%; p=0.0001). NIS immunostaining was localized on the membrane and cytoplasm of the endometrial cells. We could not find any correlation between endometrial thickness and NIS immunoexpression. Our results indicate that, in the absence of histological markers, a sterile endometrium can be recognized because of the high expressions of NIS. Moreover, NIS expressions, elevated in both sterile and menopause women, is not related to the estrogen levels, but it could be modulated by factors common to the two conditions. In conclusion, we speculate that NIS may play a role in the development of female sterility.
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http://dx.doi.org/10.14670/HH-23.549DOI Listing
May 2008

Increased pulmonary neurotrophin protein expression in idiopathic interstitial pneumonias.

Sarcoidosis Vasc Diffuse Lung Dis 2007 Mar;24(1):13-23

Dipartimento di Scienze Cardiovascolari e Respiratorie, Università di Roma La Sapienza, Ospedale Sant'Andrea, Via di Grottarossa, 1035-1039 00189 Roma.

Background And Aim Of The Study: Idiopathic interstitial pneumoniae (IIPs) are characterized by fibroblast proliferation, extracellular matrix deposition and progressive lung function impairment. Because effective therapeutic strategies still remain limited, research has been directed toward the identification of novel targets for additional therapeutic options. The neurotrophins (NTs) nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and NT-3, beside their importance in nervous, endocrine and immune system activities, participate in chronic inflammatory disorders and in repair processes.

Methods: We have investigated NT and high and low affinity NT receptor expression in IIPs using immunoblots and immunohistochemistry. Fourteen idiopatic pulmonary fibrosis/usual interstitial pneumoniae (IPF/UIP), eight non specific pneumoniae (NSIP) and eight respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) were analyzed.

Results: Immunoblots revealed that NT and high affinity NT receptor proteins were more abundantly expressed in IPF/UIP than NSIP and RB-ILD patients. In RB-ILD, a faint expression of NT-3 and NT receptors were detected. NT and NT receptor immunostaining was detected in interstitial cells from IPF/UIP, NSIP and RB-ILD patients by immunohistochemistry. Fibroblastic foci in IPF/UIP strongly stained for BDNF and its high affinity receptor TrkB and in lesser amount for NGF, NT-3 and their respective high affinity receptors TrkA and TrkC. Furthermore, in fibroblast culture derived from IPF/UIP patients, the proliferation rate of primary culture and clones derived from primary lines was stimulated by BDNF but down regulated by NT-3. In contrast, NGF did not influence IPF/UIP fibroblasts proliferation.

Conclusions: Our data suggest that that NTs may exert differential activities on lung fibroblasts and may be considered as potential regulatory molecules influencing fibroblast behavior in IPF/UIP patients. Therefore, NTs may play a role in IIPs patho-physiology representing novel potential therapeutic targets.
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March 2007

CD5+ B cells with the features of subepithelial B cells found in human tonsils.

Eur J Immunol 2007 Aug;37(8):2138-47

S.C. Oncologia Medica C, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.

This study describes a CD5+ B cell that differs from the majority of the CD5+ B cells from human tonsils. This cell, isolated from in vivo activated B cells, expressed activation markers and featured a CD23-, IgMhigh, IgDlow surface phenotype, responded to T cell-independent type-2 antigens in vitro, and was detected in the subepithelial (SE) areas, the tonsil equivalent of the splenic marginal zone (MZ). Most of the cells utilized unmutated Ig VH genes, although cells with mutated genes also were found, a finding confirmed by single-cell studies. Mutated sequences were more frequent in suspensions enriched for CD27+ cells. Repeated VDJ gene sequences were observed in different molecular clones from the same cell suspension, suggesting in situ expansion. These CD5+ B cells seem to share features with previously characterized tonsil CD5- SE B cells and differ from the majority of tonsil CD5+ B cells, which have the surface phenotype of follicular mantle B cells, lack activation markers, do not respond to T cell-independent antigens, and utilize unmutated VH genes. These data are discussed considering the present views on the origin of B cell subset populations and the relationships between MZ and B1 cells.
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http://dx.doi.org/10.1002/eji.200636887DOI Listing
August 2007

Expression of p53/HGF/c-met/STAT3 signal in fetuses with neural tube defects.

Virchows Arch 2007 Feb;450(2):203-10

Dipartimento di Patologia Umana, Policlinico Universitario, via Consolare Valeria, 1, 98125 Messina, Italy.

Neural tube defects (NTD) are morphogenetic alterations due to a defective closure of neural tube. Hepatocyte growth factor (HGF)/c-met system plays a role in morphogenesis of nervous system, lung, and kidney. HGF/c-met morphogenetic effects are mediated by signal transducers and activators of transcription (STAT)3 and both HGF and c-met genes are regulated from p53. The aim of our study was to analyze mRNA and protein expressions of p53, HGF, c-met, and STAT3 in fetuses with NTD. By reverse transcriptase-polymerase chain reaction and immunohistochemistry, we analyzed neural tissues from four NTD fetuses and the corresponding non-malformed lungs, kidneys and placentas. We found a reduced mRNA expression of HGF/c-met/STAT3 pathway, in the malformed nervous systems and placentas. The reduced expression of this pathway correlated with the absence of p53 in all these samples. On the contrary, detectable expression levels of p53, HGF, c-met, and STAT3 were observed in non-malformed lungs and kidneys obtained from the same fetuses. Comparable results were obtained by immunohistochemistry, with the exception of p53, which was undetected in all fetal tissues. In conclusion, in NTD fetuses, both the defective neural tube tissue and the placenta have a reduction in all components of the p53/HGF/c-met/STAT3 cascade. This raises the possibility of using the suppression of these genes for early diagnosis of NTD especially on chorionic villus sampling.
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http://dx.doi.org/10.1007/s00428-006-0356-5DOI Listing
February 2007

Immunoexpression of multidrug-resistance protein 2 and cyclooxygenase 2 in medullary thyroid carcinomas.

Arch Pathol Lab Med 2006 Jul;130(7):1014-9

Sezione di Endocrinologia, Dipartimento Clinico-Sperimentale di Medicina e Farmacologia, Policlinico Universitario, Messina, Italy.

Context: Chemoresistance is due to the expression of multidrug-resistance proteins (MRPs). Cyclooxygenase 2 (COX2), a key enzyme in prostaglandins synthesis, upregulates MRP1. MRP1 is overexpressed in medullary thyroid carcinomas (MTCs), but it is not involved in resistance to doxorubicin and cisplatin, which are commonly used in MTC treatment. MRP2 is specifically involved in resistance to both chemotherapeutic agents, but no data exist on the expression of MRP2 and COX2 in MTC.

Objective: To evaluate MRP2 and COX2 expressions in MTC.

Design: We analyzed immunohistochemical expression of MRP2 and COX2 in 12 MTCs and in 6 lymph node metastases. Results were correlated with pTNM and clinical stage.

Results: MRP2 and COX2 expressions were observed only in tumor samples and metastases. Nine MTCs, all pTNM stage T4, were positive for MRP2, whereas 3 MTCs, pTNM stages T2 and T3, were unreactive for MRP2. Six metastatic MTCs at stage T4 showed higher proportion of MRP2+ cells, compared with primary tumors. All 12 MTCs were positive for COX2. Three MTCs, pTNM stage T2 and T3, showed COX2 positivity in all cells. The proportion of COX2+ cells decreased with increased pTNM stage. Four out of 6 metastatic MTCs, stage T4, showed a lower proportion of COX2+ cells, compared with primary tumors. The proportion of MRP2+ cells was inversely related to the proportion of COX2+ cells.

Conclusions: MRP2 and COX2 expression correlated with pTNM stage. High MRP2 and low COX2 expression may explain resistance to doxorubicin and cisplatin, which is observed in advanced stage MTC. Evaluation of the expression pattern of these 2 proteins may be useful to predict chemosensitivity of these types of tumors.
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http://dx.doi.org/10.5858/2006-130-1014-IOMPACDOI Listing
July 2006
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