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1. Utility of the Khorana and the new-Vienna CATS prediction scores in cancer patients of the HYPERCAN cohort

Author

Marina, Marchetti, Silvia, Bolognini, Sara, Gamba, Cinzia, Giaccherini, Laura, Russo, Francesca, Schieppati, Julia, Tartari Carmen, Chiara, Ticozzi, Cristina, Verzeroli, Alfonso, Vignoli, Armando, Santoro, Giovanna, Masci, Filippo, De Braud, Antonia, Martinetti, Carlo, Tondini, Roberto, Labianca, Giampietro, Gasparini, Roberta, Sarmiento, Elisabetta, Gennaro, Mauro, Minelli, Sandro, Barni, Fausto, Petrelli, Mara, Ghilardi, Andrea, D’Alessio, Sara, Cecchini, Francesco, Giuliani, Paolo, Malighetti, Chiara, Morlotti, Daniele, Spinelli, Falanga, Anna, Verzeroli, Cristina, Giaccherini, Cinzia, Russo, Laura, Bolognini, Silvia, Gamba, Sara, Tartari, Carmen J., Schieppati, Francesca, Ticozzi, Chiara, Vignoli, Alfonso, Masci, Giovanna, Sarmiento, Roberta, Spinelli, Daniele, Malighetti, Paolo, Tondini, Carlo, Petrelli, Fausto, Giuliani, Francesco, D’Alessio, Andrea, Gasparini, Giampietro, Minelli, Mauro, De Braud, Filippo, Santoro, Armando, Labianca, Roberto, and Marchetti, Marina

Published
2023
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2. Thrombin generation predicts early recurrence in breast cancer patients

Author

Marchetti, Marina, Giaccherini, Cinzia, Masci, Giovanna, Verzeroli, Cristina, Russo, Laura, Celio, Luigi, Sarmiento, Roberta, Gamba, Sara, Tartari, Carmen J., Diani, Erika, Vignoli, Alfonso, Malighetti, Paolo, Spinelli, Daniele, Kuderer, Nicole M., Nichetti, Federico, Minelli, Mauro, Tondini, Carlo, Barni, Sandro, Giuliani, Francesco, Petrelli, Fausto, D’Alessio, Andrea, Gasparini, Giampietro, Labianca, Roberto, Santoro, Armando, De Braud, Filippo, Falanga, Anna, Schieppati, Francesca, Martinetti, Antonia, Gennaro, Elisabetta, and Ghilardi, Mara

Published
2020
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3. Utility of the Khorana and the new-Vienna CATS prediction scores in cancer patients of the HYPERCAN cohort

Author

Verzeroli, Cristina, primary, Giaccherini, Cinzia, additional, Russo, Laura, additional, Bolognini, Silvia, additional, Gamba, Sara, additional, Tartari, Carmen J., additional, Schieppati, Francesca, additional, Ticozzi, Chiara, additional, Vignoli, Alfonso, additional, Masci, Giovanna, additional, Sarmiento, Roberta, additional, Spinelli, Daniele, additional, Malighetti, Paolo, additional, Tondini, Carlo, additional, Petrelli, Fausto, additional, Giuliani, Francesco, additional, D’Alessio, Andrea, additional, Gasparini, Giampietro, additional, Minelli, Mauro, additional, De Braud, Filippo, additional, Santoro, Armando, additional, Labianca, Roberto, additional, Marchetti, Marina, additional, Falanga, Anna, additional, Marina, Marchetti, additional, Silvia, Bolognini, additional, Sara, Gamba, additional, Cinzia, Giaccherini, additional, Laura, Russo, additional, Francesca, Schieppati, additional, Julia, Tartari Carmen, additional, Chiara, Ticozzi, additional, Cristina, Verzeroli, additional, Alfonso, Vignoli, additional, Armando, Santoro, additional, Giovanna, Masci, additional, Filippo, De Braud, additional, Antonia, Martinetti, additional, Carlo, Tondini, additional, Roberto, Labianca, additional, Giampietro, Gasparini, additional, Roberta, Sarmiento, additional, Elisabetta, Gennaro, additional, Mauro, Minelli, additional, Sandro, Barni, additional, Fausto, Petrelli, additional, Mara, Ghilardi, additional, Andrea, D’Alessio, additional, Sara, Cecchini, additional, Francesco, Giuliani, additional, Paolo, Malighetti, additional, Chiara, Morlotti, additional, Daniele, Spinelli, additional, and Anna, Falanga, additional

Published
2023
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4. Hemostatic Profile and Serological Response of Patients with Immune Thrombotic Thrombocytopenic Purpura after Receiving BNT162b2 Vaccine: A Prospective Study

Author

Schieppati, Francesca, additional, Russo, Laura, additional, Gamba, Sara, additional, Galimberti, Elisa, additional, Giaccherini, Cinzia, additional, Tartari, Carmen J., additional, Bolognini, Silvia, additional, Verzeroli, Cristina, additional, Ticozzi, Chiara, additional, Barcella, Luca, additional, Marchetti, Marina, additional, and Falanga, Anna, additional

Published
2023
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5. Role of Hemostatic Biomarkers for the Identification of Patients with LONG-COVID19 Syndrome: Results from the 'Accordi' Study

Author

Ambaglio, Chiara, primary, Marchetti, Marina, additional, Benatti, Simone V, additional, Tartari, Carmen J, additional, Giaccherini, Cinzia, additional, Russo, Laura, additional, Gamba, Sara, additional, Verzeroli, Cristina, additional, Bolognini, Silvia, additional, Ticozzi, Chiara, additional, Schieppati, Francesca, additional, Venturelli, Serena, additional, Barcella, Luca, additional, Rizzi, Marco, additional, and Falanga, Anna, additional

Published
2022
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6. Inflammatory and Coagulation Biomarkers in Patients with Sars-COV2 Infection Receiving COVID-19 Convalescent Plasma: The Bergamo Registry

Author

Marchetti, Marina, primary, Palladino, Angela Maria, additional, Tartari, Carmen J, additional, Russo, Laura, additional, Giaccherini, Cinzia, additional, Gamba, Sara, additional, Bolognini, Silvia, additional, Verzeroli, Cristina, additional, Ticozzi, Chiara, additional, Cretu, Oana Cristina, additional, Schieppati, Francesca, additional, Barcella, Luca, additional, and Falanga, Anna, additional

Published
2022
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9. NPM/ALK binds and phosphorylates the RNA/DNA-binding protein PSF in anaplastic large-cell lymphoma

Author

Galietta, Annamaria, Gunby, Rosalind H., Redaelli, Sara, Stano, Paola, Carniti, Cristiana, Bachi, Angela, Tucker, Philip W., Tartari, Carmen J., Huang, Ching-Jung, Colombo, Emanuela, Pulford, Karen, Puttini, Miriam, Piazza, Rocco G., Ruchatz, Holger, Villa, Antonello, Donella-Deana, Arianna, Marin, Oriano, Perrotti, Danilo, and Gambacorti-Passerini, Carlo

Published
2007
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10. Thrombin Generation and D-Dimer Significantly Predict for Early Disease Progression and Mortality in Patients with Gastrointestinal Cancer

Author

Pesenti, Marina, primary, Marchetti, Marina, additional, Giaccherini, Cinzia, additional, Verzeroli, Cristina, additional, Russo, Laura, additional, Gasparini, Giampietro, additional, Sarmiento, Roberta, additional, Celio, Luigi, additional, Masci, Giovanna, additional, Gamba, Sara, additional, Gomez-Rosas, Patricia, additional, Schillaci, Nadia FJ, additional, Bolognini, Silvia, additional, Tartari, Carmen J, additional, Diani, Erika, additional, Vignoli, Alfonso, additional, Tondini, Carlo, additional, Barni, Sandro, additional, Giuliani, Francesco, additional, Petrelli, Fausto, additional, D'Alessio, Andrea, additional, De Braud, Filippo, additional, Santoro, Armando, additional, Labianca, Roberto, additional, and Falanga, Anna, additional

Published
2020
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11. A Thrombotic Biomarker-Based Risk Assessment Scoring Model for Disease Recurrence in Breast Cancer Patient Candidate to Systemic Chemotherapy

Author

Falanga, Anna, primary, Giaccherini, Cinzia, additional, Marchetti, Marina, additional, Masci, Giovanna, additional, Verzeroli, Cristina, additional, Russo, Laura, additional, Celio, Luigi, additional, Sarmiento, Roberta, additional, Gamba, Sara, additional, Tartari, Carmen J, additional, Diani, Erika, additional, Vignoli, Alfonso, additional, Malighetti, Paolo, additional, Spinelli, Daniele, additional, Tondini, Carlo, additional, Barni, Sandro, additional, Giuliani, Francesco, additional, Petrelli, Fausto, additional, D'Alessio, Andrea, additional, Gasparini, Giampietro, additional, De Braud, Filippo, additional, Santoro, Armando, additional, and Labianca, Roberto, additional

Published
2019
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12. Thrombotic Risk Assessment in a Prospective Cohort of Newly Diagnosed Ambulatory Cancer Patients Candidate to Chemotherapy

Author

Falanga, Anna, primary, Verzeroli, Cristina, additional, Marchetti, Marina, additional, Giaccherini, Cinzia, additional, Russo, Laura, additional, Masci, Giovanna, additional, Celio, Luigi, additional, Sarmiento, Roberta, additional, Gamba, Sara, additional, Tartari, Carmen J, additional, Diani, Erika, additional, Vignoli, Alfonso, additional, Malighetti, Paolo, additional, Spinelli, Daniele, additional, Tondini, Carlo, additional, Barni, Sandro, additional, Giuliani, Francesco, additional, Petrelli, Fausto, additional, D'Alessio, Andrea, additional, Gasparini, Giampietro, additional, De Braud, Filippo, additional, Santoro, Armando, additional, and Labianca, Roberto, additional

Published
2019
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13. Platelet haemostatic properties in β-thalassaemia: The effect of blood transfusion

Author

Trinchero, Alice, Marchetti, Marina, Giaccherini, Cinzia, Tartari, Carmen J., Russo, Laura, Falanga, Anna, Trinchero, A, Marchetti, M, Giaccherini, C, Tartari, C, Russo, L, and Falanga, A

Subjects
Adult, Blood Platelets, Male, Adolescent, beta-Thalassemia, Middle Aged, Platelet Adhesiveness, Child, Preschool, Splenectomy, Humans, β-thalassaemia, platelet aggregation, thrombin generation, blood transfusion, tissue factor, Original Article, Blood Transfusion, Female, Child
Abstract

Background. Patients with thalassaemia may have thromboembolic events and, even without thrombosis, they have a subclinical hypercoagulable state. In this setting, several coagulation laboratory abnormalities have been described, but thus far no studies have explored the contribution of platelet adhesive and procoagulant properties to blood clotting activation. In this study, we dissected the platelet procoagulant effect and influence of blood transfusions on haemostasis and platelet function in thalassaemic patients. Material and methods. Sixteen subjects with thalassaemia were studied (9 with transfusion-dependent β-thalassaemia, 7 "trait" carriers). Splenectomised and non-splenectomised patients undergoing blood transfusion were compared. All splenectomised patients were then compared to "trait" carriers and to healthy controls (n=9). The following parameters were measured in transfusion-dependent patients before and after monthly transfusions and compared to those of controls: levels of platelet surface activation markers (P-selectin, tissue factor, and fibrinogen), whole blood platelet aggregation, tissue factor or adenosine diphosphate (ADP)-induced platelet thrombin generation (TG) potential, and D-dimer. Results. Before transfusion, platelets from splenectomised patients showed significantly higher ADP-induced tissue factor expression, ADP- and collagen-induced platelet aggregation and TG potential than those from non-splenectomised patients and controls. Blood transfusion in splenectomised patients reduced platelet activation, aggregation and TG potential. Discussion. Splenectomised patients with β-thalassaemia had a prothrombotic state, characterised by enhanced platelet reactivity and function, and high platelet-induced TG potential. One hour after blood transfusions platelet and coagulation parameters improved, supporting the hypothesis that transfusion might have a protective role on platelet haemostatic status.

Published
2017

14. Pre-Chemotherapy Levels of Hemostatic Biomarkers and Prediction of Prognosis in Newly Diagnosed Metastatic Cancer Patients from the Hypercan Study

Author

Falanga, Anna, primary, Giaccherini, Cinzia, additional, Verzeroli, Cristina, additional, Marchetti, Marina, additional, Russo, Laura, additional, Masci, Giovanna, additional, Celio, Luigi, additional, Merelli, Barbara, additional, Sarmiento, Roberta, additional, Ghilardi, Mara, additional, Tartari, Carmen J, additional, Brevi, Shenaz, additional, Caldara, Gloria, additional, Gamba, Sara, additional, Malighetti, Paolo, additional, Spinelli, Daniele, additional, Santoro, Armando, additional, De Braud, Filippo, additional, Gasparini, Giampietro, additional, Giuliani, Francesco, additional, Barni, Sandro, additional, D'Alessio, Andrea, additional, and Labianca, Roberto, additional

Published
2018
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15. Hypercoagulation screening as an innovative tool for risk assessment, early diagnosis and prognosis in cancer: the HYPERCAN study

Author

Falanga, Anna, primary, Santoro, Armando, additional, Labianca, Roberto, additional, De Braud, Filippo, additional, Gasparini, Giampietro, additional, D’Alessio, Andrea, additional, Barni, Sandro, additional, Iacoviello, Licia, additional, Falanga, Anna, additional, Barcella, Luca, additional, Brevi, Shenaz, additional, Gamba, Sara, additional, Giaccherini, Cinzia, additional, Marchetti, Marina, additional, Milesi, Viola, additional, Piras, Francesca, additional, Rio, Francesca, additional, Russo, Laura, additional, Tartari, Carmen J., additional, Tessarolo, Serena, additional, Verzeroli, Cristina, additional, Vignoli, Alfonso, additional, Donati, Maria Benedetta, additional, Masci, Giovanna, additional, Nardozza, Angelo, additional, Tondini, Carlo, additional, Mandalà, Mario, additional, Merelli, Barbara, additional, Celio, Luigi, additional, Martinetti, Antonia, additional, De Maria, Ilaria, additional, Meoni, Guido, additional, Minelli, Mauro, additional, Sarmiento, Roberta, additional, Tarantini, Paola, additional, Oliva, Nadia, additional, Ghilardi, Mara, additional, Malighetti, Paolo, additional, Spinelli, Daniele, additional, and Sampietro, Giuseppe, additional

Published
2016
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17. Hypercoagulation Screening As a Marker of Thrombosis and Poor Disease Prognosis in Cancer Patients: The Hypercan Prospective Study

Author

Marchetti, Marina R, primary, Masci, Giovanna, additional, Santoro, Armando, additional, de Braud, Filippo, additional, Celio, Luigi, additional, Labianca, Roberto, additional, Mandalà, Mario, additional, Merelli, Barbara, additional, Tondini, Carlo, additional, Gasparini, Giampietro, additional, Sarmiento, Roberta, additional, Tartari, Carmen J, additional, Giaccherini, Cinzia, additional, Piras, Francesca, additional, Verzeroli, Cristina, additional, Barcella, Luca, additional, Vignoli, Alfonso, additional, and Falanga, Anna, additional

Published
2014
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22. Structural Insights into the ATP Binding Pocket of the Anaplastic Lymphoma Kinase by Site-Directed Mutagenesis, Inhibitor Binding Analysis, and Homology Modeling

Author

Gunby, Rosalind H., primary, Ahmed, Shaheen, additional, Sottocornola, Roberta, additional, Gasser, Marc, additional, Redaelli, Sara, additional, Mologni, Luca, additional, Tartari, Carmen J, additional, Belloni, Valentina, additional, Gambacorti-Passerini, Carlo, additional, and Scapozza, Leonardo, additional

Published
2006
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23. Unique Substrate Specificity of Anaplastic Lymphoma Kinase (ALK): Development of Phosphoacceptor Peptides for the Assay of ALK Activity

Author

Donella-Deana, Arianna, primary, Marin, Oriano, additional, Cesaro, Luca, additional, Gunby, Rosalind H., additional, Ferrarese, Anna, additional, Coluccia, Addolorata M. L., additional, Tartari, Carmen J., additional, Mologni, Luca, additional, Scapozza, Leonardo, additional, Gambacorti-Passerini, Carlo, additional, and Pinna, Lorenzo A., additional

Published
2005
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24. Prospective Evaluation of Thrombo-Hemorrhagic Events and Hypercoagulation Markers in Patients with Acute Promyelocytic Leukemia (APL) Receiving All-Trans Retinoic Acid (ATRA) Plus Chemotherapy

Author

Falanga, Anna, Russo, Laura, Marchetti, Marina, Tartari, Carmen J, Castellani, Laura, Di Bona, Eros, Woodhams, Barry, Rambaldi, Alessandro, and Lo Coco, Francesco

Abstract

Introduction:Patients with APL typically present with a life-threatening thrombo-hemorrhagic syndrome (THS), due to the consumption of coagulation factors and platelets, secondary to clotting activation. Presently, all- transretinoic acid (ATRA) has greatly improved the management of APL, but has not significantly changed the rate of early hemorrhagic deaths and may actually promote thrombosis.Characterizing the coagulopathy and identifying predictive markers of bleeding/clotting complications remain critical issues. Aim: In newly diagnosed APL patients, in the first month after diagnosis, we wanted prospectively to: 1. register thrombo/hemorrhagic events; 2. evaluate, the profiles of circulating hypercoagulation markers and the molecular expression of Tissue Factor (TF), before and during ATRA therapy; and 3. verify whether changes in the biomarker profiles correlate with the occurrence of thrombo-hemorragic events. Methods: Sixty consecutive APL patients receiving ATRA+Idarubicin for remission induction (GIMEMA protocol AIDA2000) were enrolled from January 2005 to March 2017. Blood samples from a subgroup of 30 patients (F/M= 11/19) were obtained at the onset (T0), and on days 7, 14 and 28 (T7, T14, T28) of remission induction therapy. Plasma levels of activated factor VII-antithrombin complex (FVIIa-AT), thrombin-antithrombin complex (TAT), and D-dimer were measured by ELISA; TF mRNA levels in peripheral blood mononuclear cells (PBMC) was evaluated in 16 APL patients by real time-polymerase chain reaction. Results: At enrolment (T0), before starting ATRA, 13.3% of APL patients presented with early major hemorrhages, including 3 (5%) fatal intracranial bleeding and 5 (8.3%) non-fatal major bleeding (i.e. gengivorrhagia, gastrointestinal bleeding, epistaxis, menorrhagia). At T0, the prevalence of thrombosis in the total group of 60 APL patients was 6.6%, including 1 fatal pulmonary embolism (PE), 2 non-fatal venous thrombosis (1 PE, 1 lower limb deep vein thrombosis [DVT]), and 1 non-fatal arterial thrombosis (acute myocardial infarction [AMI]). During ATRA therapy, 8.3% of APL patients developed major bleeding: including 2 fatal intracranial hemorrhage after 3 days of ATRA treatment and 3 non-fatal major bleeding (i.e. gengivorrhagia, epistaxis, menorrhagia) after 7, 10 and 17 days of ATRA. Two more patients developed non-fatal thrombosis (i.e. 1 AMI and 1 DVT) after 9 and 20 days of ATRA treatment, respectively. The laboratory sub-study of 30 subjects showed that, at T0, before starting therapy, the plasma levels of FVIIa-AT, TAT and D-dimer were significantly higher in APL patients compared to controls (p<0.05). During induction therapy with ATRA, the levels of TAT and D-dimer significantly (p<0.05) and progressively decreased at T7 and T14, reaching the lowest value at 28 days. Differently, FVIIa-AT levels were unchanged at T7 and T14, and dropped significantly only at T28 (p<0.05 vs T0). In addition, in APL PBMC from 16 patients, the levels of TF mRNA, initially elevated compared to healthy control PBMC (p<0.05), during induction therapy were significantly decreased by 68% and 90%, at T7 and T28, respectively. In these 16 APL patients, a statistically significant correlation (p<0.05) was found between decrease in TF mRNA and FVIIa-AT levels during ATRA therapy. Of the 30 patients included in the laboratory sub-study, 3 had non-fatal thrombosis at diagnosis, no major hemorrhages were recorded. The predictive value of THS of thrombotic markers could not be calculated. Conclusions: Our data show a significant rate (31%) of severe (fatal and non-fatal) thrombo/hemorrhagic events in our cohort of APL patients in the first 3 weeks of diagnosis, with 4 fatal events (6.6%) occurring early, before starting ATRA. Laboratory data show for the first time that, while TAT and D-dimer confirm to be sensitive to ATRA downregulation, differently FVIIa-AT levels persist at high level over time, showing the perseverance of TF-dependent clotting activation. Future large prospective clinical trials should include FVIIa-AT to evaluate persistent clotting activation during ATRA.

Published
2017
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25. Thrombotic biomarkers for risk prediction of malignant disease recurrence in patients with early stage breast cancer.

Author

Giaccherini C, Marchetti M, Masci G, Verzeroli C, Russo L, Celio L, Sarmiento R, Gamba S, Tartari CJ, Diani E, Vignoli A, Malighetti P, Spinelli D, Tondini C, Barni S, Giuliani F, Petrelli F, D'Alessio A, Gasparini G, De Braud F, Santoro A, Labianca R, and Falanga A

Subjects
Biomarkers, Biomarkers, Tumor, Humans, Neoplasm Recurrence, Local, Prognosis, Prospective Studies, Breast Neoplasms diagnosis, Breast Neoplasms therapy
Abstract

In cancer patients, hypercoagulability is a common finding. It has been associated with an increased risk of venous thromboembolism, but also to tumor proliferation and progression. In this prospective study of a large cohort of breast cancer patients, we aimed to evaluate whether pre-chemotherapy abnormalities in hemostatic biomarkers levels: (i) are associated with breast cancer-specific clinico-pathological features; and (ii) can predict for disease recurrence. D-dimer, fibrinogen, prothrombin fragment 1+2, and FVIIa/antithrombin levels were measured in 701 early-stage resected breast cancer patients candidate to adjuvant chemotherapy and prospectively enrolled in the HYPERCAN study. Significant prognostic parameters for disease recurrence were identified by Cox regression multivariate analysis and used for generating a risk assessment model. Pre-chemotherapy D-dimer, fibrinogen, and pro-thrombin fragment 1+2 levels were significantly associated with tumor size and lymph node metastasis. After 3.4 years of follow up, 71 patients experienced a recurrence. Cox multivariate analysis identified prothrombin fragment 1+2, tumor size, and Luminal B HER2-negative or triple negative molecular subtypes as independent risk factors for disease recurrence. Based on these variables, we generated a risk assessment model that significantly differentiated patients at low- and high-risk of recurrence (cumulative incidence: 6.2 vs 20.7%; Hazard Ratio=3.5; P <0.001). Our prospective clinical and laboratory data from the HYPERCAN study were crucial for generating a scoring model for assessing risk of disease recurrence in resected breast cancer patients, candidate to systemic chemotherapy. This finding stimulates future investigations addressing the role of plasma prothrombin fragment 1+2 in the management of breast cancer patients to provide the rationale for new therapeutic strategies. (The HYPERCAN study is registered at clinicaltrials.gov identifier 02622815 )., (Copyright© 2020 Ferrata Storti Foundation.)

Published
2020
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26. Platelet haemostatic properties in β-thalassaemia: the effect of blood transfusion.

Author

Trinchero A, Marchetti M, Giaccherini C, Tartari CJ, Russo L, and Falanga A

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Blood Platelets metabolism, Blood Transfusion, Platelet Adhesiveness, Splenectomy, beta-Thalassemia blood, beta-Thalassemia therapy
Abstract

Background: Patients with thalassaemia may have thromboembolic events and, even without thrombosis, they have a subclinical hypercoagulable state. In this setting, several coagulation laboratory abnormalities have been described, but thus far no studies have explored the contribution of platelet adhesive and procoagulant properties to blood clotting activation. In this study, we dissected the platelet procoagulant effect and influence of blood transfusions on haemostasis and platelet function in thalassaemic patients., Material and Methods: Sixteen subjects with thalassaemia were studied (9 with transfusion-dependent β-thalassaemia, 7 "trait" carriers). Splenectomised and non-splenectomised patients undergoing blood transfusion were compared. All splenectomised patients were then compared to "trait" carriers and to healthy controls (n=9). The following parameters were measured in transfusion-dependent patients before and after monthly transfusions and compared to those of controls: levels of platelet surface activation markers (P-selectin, tissue factor, and fibrinogen), whole blood platelet aggregation, tissue factor or adenosine diphosphate (ADP)-induced platelet thrombin generation (TG) potential, and D-dimer., Results: Before transfusion, platelets from splenectomised patients showed significantly higher ADP-induced tissue factor expression, ADP- and collagen-induced platelet aggregation and TG potential than those from non-splenectomised patients and controls. Blood transfusion in splenectomised patients reduced platelet activation, aggregation and TG potential., Discussion: Splenectomised patients with β-thalassaemia had a prothrombotic state, characterised by enhanced platelet reactivity and function, and high platelet-induced TG potential. One hour after blood transfusions platelet and coagulation parameters improved, supporting the hypothesis that transfusion might have a protective role on platelet haemostatic status.

Published
2017
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27. The ALK gene, an attractive target for inhibitor development.

Author

Tartari CJ, Scapozza L, and Gambacorti-Passerini C

Subjects
Anaplastic Lymphoma Kinase, Animals, Antineoplastic Agents chemistry, Humans, Neoplasms drug therapy, Neoplasms metabolism, Protein Kinase Inhibitors chemistry, Receptor Protein-Tyrosine Kinases metabolism, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Drug Discovery, Neoplasms enzymology, Protein Kinase Inhibitors pharmacology, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases genetics
Abstract

Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase that belongs to the Insulin receptor subfamily involved as full length receptor in neural development. Even if the expression of ALK protein is down-regulated in the adults, the ALK full length is expressed in different types of tumors. Moreover, chromosomal rearrangements, involving the alk gene, can occur leading the formation of different ALK fusion proteins characterized by the kinase domain of ALK fused to several partners that determine cellular localization. Structural investigation and characterization of the ALK kinase domain in absence of its crystal structure constituted the basis of development of ALK small molecule inhibitors. Here, we described normal function of the ALK receptor and its role in tumors; formation of the constitutively activated ALK fusion proteins and we reported an update of developed small molecule inhibitors of the ALK kinase activity.

Published
2011
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28. Dissection of the RET/β-catenin interaction in the TPC1 thyroid cancer cell line.

Author

Tartari CJ, Donadoni C, Manieri E, Mologni L, Mina PD, Villa A, and Gambacorti-Passerini C

Abstract

The RET receptor tyrosine kinase is a member of the cadherin superfamily and plays a pivotal role in cell survival, differentiation and proliferation. Currently, 12 ret/ptc chimeric oncogenes, characterized by the fusion between the intracellular domain of RET and different activating genes, which can cause ligand-independent dimerization and constitutive activation, have been described. β-catenin is usually involved in the maintenance of cell-to-cell adhesion and mediates the Wnt/β-catenin pathway important during embryogenesis and in cellular malignant transformation. Recently, a novel mechanism of RET-mediated function through the β-catenin pathway has been reported in multiple endocrine neoplasia type 2 and in sporadic thyroid carcinomas. Here, we investigated the effects of the ZD6474, a small molecule RET-inhibitor, on RET/β-catenin interaction. We confirmed the ZD6474 mediated-inhibition of recombinant RET kinase and of growth of cells expressing RET/PTC. Interestingly, we firstly observed reduced cellular mobility and changed morphology of TPC1 treated cells suggesting that RET-inhibitor could affect β-catenin cellular distribution as resulted in its co-immunoprecipitation with E-cadherin. We further investigated this hypothesis showing that TPC1 treated cells displayed predominantly β-catenin cytosolic localization. Surprisingly, RET and β-catenin co-immunoprecipitated in both ZD6474-treated and untreated TPC1 cells, suggesting that RET/β-catenin interaction might not be affected by RET kinase inactivation. All together these results suggest that RET kinase activation is crucial for β-catenin stabilization (pY654), localization and its signaling pathway activation but not for β-catenin/RET physical interactions, in human papillary thyroid carcinomas. In conclusion, ZD6474, by inhibiting RET kinase, down-modulates β-catenin pathway leading its recruitment to the membrane by E-cadherin.

Published
2011

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