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Allogeneic hematopoietic stem cell transplantation (HSCT) offers potentially curative treatment for many children with high-risk or relapsed acute leukemia (AL), thanks to the combination of intense preparative radio/chemotherapy and the graft-versus-leukemia (GvL) effect. Over the years, progress in high-resolution donor typing, choice of conditioning regimen, graft-versus-host disease (GvHD) prophylaxis and supportive care measures have continuously improved overall transplant outcome, and recent successes using alternative donors have extended the potential application of allotransplantation to most patients. In addition, the importance of minimal residual disease (MRD) before and after transplantation is being increasingly clarified and MRD-directed interventions may be employed to further ameliorate leukemia-free survival after allogeneic HSCT. These advances have occurred in parallel with continuous refinements in chemotherapy protocols and the development of targeted therapies, which may redefine the indications for HSCT in the coming years. This review discusses the role of HSCT in childhood AL by analysing transplant indications in both acute lymphoblastic and acute myeloid leukemia, together with current and most promising strategies to further improve transplant outcome, including optimization of conditioning regimen and MRD-directed interventions.
Mattia Algeri; Pietro Merli; Franco Locatelli; Daria Pagliara. The Role of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Leukemia. Journal of Clinical Medicine 2021, 10, 3790 .
AMA StyleMattia Algeri, Pietro Merli, Franco Locatelli, Daria Pagliara. The Role of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Leukemia. Journal of Clinical Medicine. 2021; 10 (17):3790.
Chicago/Turabian StyleMattia Algeri; Pietro Merli; Franco Locatelli; Daria Pagliara. 2021. "The Role of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Leukemia." Journal of Clinical Medicine 10, no. 17: 3790.
Nucleophosmin (NPM1) is a nucleocytoplasmic shuttling protein, predominantly located in the nucleolus, that regulates a multiplicity of different biological processes. NPM1 localization in the cell is finely tuned by specific signal motifs, with two tryptophan residues (Trp) being essential for the nucleolar localization. In acute myeloid leukemia (AML), several NPM1 mutations have been reported, all resulting in cytoplasmic delocalization, but the putative biological and clinical significance of different variants are still debated. We explored HOXA and HOXB gene expression profile in AML patients and found a differential expression between NPM1 mutations inducing the loss of two (A-like) Trp residues and those determining the loss of one Trp residue (non-A-like). We thus expressed NPM1 A-like- or non-A-like-mutated vectors in AML cell lines finding that NPM1 partially remained in the nucleolus in the non-A-like NPM1-mutated cells. As a result, only in A-like-mutated cells we detected HOXA5, HOXA10, and HOXB5 hyper-expression and p14ARF/p21/p53 pathway deregulation, leading to reduced sensitivity to the treatment with either chemotherapy or Venetoclax, as compared to non-A-like cells. Overall, we identified that the NPM1 mutational status mediates crucial biological characteristics of AML cells, providing the basis for further sub-classification and, potentially, management of this subgroup of patients.
Claudia Tregnago; Maddalena Benetton; Davide Padrin; Katia Polato; Giulia Borella; Ambra Da Ros; Anna Marchetti; Elena Porcù; Francesca Del Bufalo; Cristina Mecucci; Franco Locatelli; Martina Pigazzi. NPM1 Mutational Status Underlines Different Biological Features in Pediatric AML. Cancers 2021, 13, 3457 .
AMA StyleClaudia Tregnago, Maddalena Benetton, Davide Padrin, Katia Polato, Giulia Borella, Ambra Da Ros, Anna Marchetti, Elena Porcù, Francesca Del Bufalo, Cristina Mecucci, Franco Locatelli, Martina Pigazzi. NPM1 Mutational Status Underlines Different Biological Features in Pediatric AML. Cancers. 2021; 13 (14):3457.
Chicago/Turabian StyleClaudia Tregnago; Maddalena Benetton; Davide Padrin; Katia Polato; Giulia Borella; Ambra Da Ros; Anna Marchetti; Elena Porcù; Francesca Del Bufalo; Cristina Mecucci; Franco Locatelli; Martina Pigazzi. 2021. "NPM1 Mutational Status Underlines Different Biological Features in Pediatric AML." Cancers 13, no. 14: 3457.
Anna Maria Testi; Sara Mohamed; Daniela Diverio; Alfonso Piciocchi; Giuseppe Menna; Carmelo Rizzari; Fabio Timeus; Concetta Micalizzi; Luca Lo Nigro; Nicola Santoro; Riccardo Masetti; Maria Vittoria Micheletti; Ottavio Ziino; Daniela Onofrillo; Saverio Ladogana; Caterina Putti; Paolo Pierani; Valentina Arena; Marco Zecca; Robin Foà; Franco Locatelli. Outcome of relapsed/refractory acute promyelocytic leukaemia in children, adolescents and young adult patients — a 25‐year Italian experience. British Journal of Haematology 2021, 1 .
AMA StyleAnna Maria Testi, Sara Mohamed, Daniela Diverio, Alfonso Piciocchi, Giuseppe Menna, Carmelo Rizzari, Fabio Timeus, Concetta Micalizzi, Luca Lo Nigro, Nicola Santoro, Riccardo Masetti, Maria Vittoria Micheletti, Ottavio Ziino, Daniela Onofrillo, Saverio Ladogana, Caterina Putti, Paolo Pierani, Valentina Arena, Marco Zecca, Robin Foà, Franco Locatelli. Outcome of relapsed/refractory acute promyelocytic leukaemia in children, adolescents and young adult patients — a 25‐year Italian experience. British Journal of Haematology. 2021; ():1.
Chicago/Turabian StyleAnna Maria Testi; Sara Mohamed; Daniela Diverio; Alfonso Piciocchi; Giuseppe Menna; Carmelo Rizzari; Fabio Timeus; Concetta Micalizzi; Luca Lo Nigro; Nicola Santoro; Riccardo Masetti; Maria Vittoria Micheletti; Ottavio Ziino; Daniela Onofrillo; Saverio Ladogana; Caterina Putti; Paolo Pierani; Valentina Arena; Marco Zecca; Robin Foà; Franco Locatelli. 2021. "Outcome of relapsed/refractory acute promyelocytic leukaemia in children, adolescents and young adult patients — a 25‐year Italian experience." British Journal of Haematology , no. : 1.
B‐cell acute lymphoblastic leukaemia (B‐ALL) reprograms the surrounding bone marrow (BM) stroma to create a leukaemia‐supportive niche. To elucidate the contribution of immune cells to the leukaemic microenvironment, we investigated the involvement of monocyte/macrophage compartments, as well as several recruitment pathways in B‐ALL development. Immunohistochemistry analyses showed that CD68‐expressing macrophages were increased in leukaemic BM biopsies, compared to controls and predominantly expressed the M2‐like markers CD163 and CD206. Furthermore, the "non‐classical" CD14+CD16++ monocyte subset, expressing high CX3CR1 levels, was significantly increased in B‐ALL patients' peripheral blood. CX3CL1 was shown to be significantly upregulated in leukaemic BM plasma, thus providing an altered migratory pathway possibly guiding NC monocyte recruitment into the BM. Additionally, the monocyte/macrophage chemoattractant chemokine ligand 2 (CCL2) strongly increased in leukaemic BM plasma, possibly because of the interaction of leukaemic cells with mesenchymal stromal cells and vascular cells and due to a stimulatory effect of leukaemia‐related inflammatory mediators. C5a, a macrophage chemoattractant and M2‐polarizing factor, further appeared to be upregulated in the leukaemic BM, possibly as an effect of PTX3 decrease, that could unleash complement cascade activation. Overall, deregulated monocyte/macrophage compartments are part of the extensive BM microenvironment remodelling at B‐ALL diagnosis and could represent valuable targets for novel treatments to be coupled with classical chemotherapy.
Erica Dander; Alessandra Fallati; Tamara Gulić; Fabio Pagni; Stefania Gaspari; Daniela Silvestri; Giulia Cricrì; Gloria Bedini; Federica Portale; Chiara Buracchi; Rita Starace; Fabio Pasqualini; Mariella D'Angiò; Lisa Brizzolara; Oscar Maglia; Alberto Mantovani; Cecilia Garlanda; Maria Grazia Valsecchi; Franco Locatelli; Andrea Biondi; Barbara Bottazzi; Paola Allavena; Giovanna D'Amico. Monocyte–macrophage polarization and recruitment pathways in the tumour microenvironment of B‐cell acute lymphoblastic leukaemia. British Journal of Haematology 2021, 193, 1157 -1171.
AMA StyleErica Dander, Alessandra Fallati, Tamara Gulić, Fabio Pagni, Stefania Gaspari, Daniela Silvestri, Giulia Cricrì, Gloria Bedini, Federica Portale, Chiara Buracchi, Rita Starace, Fabio Pasqualini, Mariella D'Angiò, Lisa Brizzolara, Oscar Maglia, Alberto Mantovani, Cecilia Garlanda, Maria Grazia Valsecchi, Franco Locatelli, Andrea Biondi, Barbara Bottazzi, Paola Allavena, Giovanna D'Amico. Monocyte–macrophage polarization and recruitment pathways in the tumour microenvironment of B‐cell acute lymphoblastic leukaemia. British Journal of Haematology. 2021; 193 (6):1157-1171.
Chicago/Turabian StyleErica Dander; Alessandra Fallati; Tamara Gulić; Fabio Pagni; Stefania Gaspari; Daniela Silvestri; Giulia Cricrì; Gloria Bedini; Federica Portale; Chiara Buracchi; Rita Starace; Fabio Pasqualini; Mariella D'Angiò; Lisa Brizzolara; Oscar Maglia; Alberto Mantovani; Cecilia Garlanda; Maria Grazia Valsecchi; Franco Locatelli; Andrea Biondi; Barbara Bottazzi; Paola Allavena; Giovanna D'Amico. 2021. "Monocyte–macrophage polarization and recruitment pathways in the tumour microenvironment of B‐cell acute lymphoblastic leukaemia." British Journal of Haematology 193, no. 6: 1157-1171.
We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell–depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.
Luisa Strocchio; Daria Pagliara; Mattia Algeri; Giuseppina Li Pira; Francesca Rossi; Valentina Bertaina; Giovanna Leone; Rita Maria Pinto; Marco Andreani; Emanuele Agolini; Katia Girardi; Stefania Gaspari; Lavinia Grapulin; Francesca del Bufalo; Antonio Novelli; Pietro Merli; Franco Locatelli. HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia. Blood Advances 2021, 5, 1333 -1339.
AMA StyleLuisa Strocchio, Daria Pagliara, Mattia Algeri, Giuseppina Li Pira, Francesca Rossi, Valentina Bertaina, Giovanna Leone, Rita Maria Pinto, Marco Andreani, Emanuele Agolini, Katia Girardi, Stefania Gaspari, Lavinia Grapulin, Francesca del Bufalo, Antonio Novelli, Pietro Merli, Franco Locatelli. HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia. Blood Advances. 2021; 5 (5):1333-1339.
Chicago/Turabian StyleLuisa Strocchio; Daria Pagliara; Mattia Algeri; Giuseppina Li Pira; Francesca Rossi; Valentina Bertaina; Giovanna Leone; Rita Maria Pinto; Marco Andreani; Emanuele Agolini; Katia Girardi; Stefania Gaspari; Lavinia Grapulin; Francesca del Bufalo; Antonio Novelli; Pietro Merli; Franco Locatelli. 2021. "HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia." Blood Advances 5, no. 5: 1333-1339.
PURPOSE Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MATERIALS AND METHODS MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10−4), and high (≥ 5 × 10−4). RESULTS EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively ( P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively ( P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively ( P < .0001), while for myeloid-style–treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). CONCLUSION This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.
Janine Stutterheim; Inge M. van der Sluis; Paola de Lorenzo; Julia Alten; Philip Ancliffe; Andishe Attarbaschi; Benoit Brethon; Andrea Biondi; Myriam Campbell; Giovanni Cazzaniga; Gabriele Escherich; Alina Ferster; Rishi S. Kotecha; Birgitte Lausen; Chi Kong Li; Luca Lo Nigro; Franco Locatelli; Rolf Marschalek; Claus Meyer; Martin Schrappe; Jan Stary; Ajay Vora; Jan Zuna; Vincent H. J. van der Velden; Tomasz Szczepanski; Maria Grazia Valsecchi; Rob Pieters. Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol. Journal of Clinical Oncology 2021, 39, 652 -662.
AMA StyleJanine Stutterheim, Inge M. van der Sluis, Paola de Lorenzo, Julia Alten, Philip Ancliffe, Andishe Attarbaschi, Benoit Brethon, Andrea Biondi, Myriam Campbell, Giovanni Cazzaniga, Gabriele Escherich, Alina Ferster, Rishi S. Kotecha, Birgitte Lausen, Chi Kong Li, Luca Lo Nigro, Franco Locatelli, Rolf Marschalek, Claus Meyer, Martin Schrappe, Jan Stary, Ajay Vora, Jan Zuna, Vincent H. J. van der Velden, Tomasz Szczepanski, Maria Grazia Valsecchi, Rob Pieters. Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol. Journal of Clinical Oncology. 2021; 39 (6):652-662.
Chicago/Turabian StyleJanine Stutterheim; Inge M. van der Sluis; Paola de Lorenzo; Julia Alten; Philip Ancliffe; Andishe Attarbaschi; Benoit Brethon; Andrea Biondi; Myriam Campbell; Giovanni Cazzaniga; Gabriele Escherich; Alina Ferster; Rishi S. Kotecha; Birgitte Lausen; Chi Kong Li; Luca Lo Nigro; Franco Locatelli; Rolf Marschalek; Claus Meyer; Martin Schrappe; Jan Stary; Ajay Vora; Jan Zuna; Vincent H. J. van der Velden; Tomasz Szczepanski; Maria Grazia Valsecchi; Rob Pieters. 2021. "Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol." Journal of Clinical Oncology 39, no. 6: 652-662.
MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.
Oscar Lopez-Nunez; Rita Alaggio; Ivy John; Andrea Ciolfi; Lucia Pedace; Angela Mastronuzzi; Francesca Gianno; Felice Giangaspero; Sabrina Rossi; Vittoria Donofrio; Giuseppe Cinalli; Lea Surrey; Marco Tartaglia; Franco Locatelli; Evelina Miele. Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling. Cancers 2021, 13, 706 .
AMA StyleOscar Lopez-Nunez, Rita Alaggio, Ivy John, Andrea Ciolfi, Lucia Pedace, Angela Mastronuzzi, Francesca Gianno, Felice Giangaspero, Sabrina Rossi, Vittoria Donofrio, Giuseppe Cinalli, Lea Surrey, Marco Tartaglia, Franco Locatelli, Evelina Miele. Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling. Cancers. 2021; 13 (4):706.
Chicago/Turabian StyleOscar Lopez-Nunez; Rita Alaggio; Ivy John; Andrea Ciolfi; Lucia Pedace; Angela Mastronuzzi; Francesca Gianno; Felice Giangaspero; Sabrina Rossi; Vittoria Donofrio; Giuseppe Cinalli; Lea Surrey; Marco Tartaglia; Franco Locatelli; Evelina Miele. 2021. "Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling." Cancers 13, no. 4: 706.
Tumor-infiltrating CD8+ T cells have been shown to play a crucial role in controlling tumor progression. However, the recruitment and activation of these immune cells at the tumor site are strictly dependent on several factors, including the presence of dendritic cells (DCs), the main orchestrators of the antitumor immune responses. Among the various DC subsets, the role of cDC1s has been demonstrated in several preclinical experimental mouse models. In addition, the high density of tumor-infiltrating cDC1s has been associated with improved survival in many cancer patients. The ability of cDC1s to modulate antitumor activity depends on their interaction with other immune populations, such as NK cells. This evidence has led to the development of new strategies aimed at increasing the abundance and activity of cDC1s in tumors, thus providing attractive new avenues to enhance antitumor immunity for both established and novel anticancer immunotherapies. In this review, we provide an overview of the various subsets of DCs, focusing in particular on the role of cDC1s, their ability to interact with other intratumoral immune cells, and their prognostic significance on solid tumors. Finally, we outline key therapeutic strategies that promote the immunogenic functions of DCs in cancer immunotherapy.
Valeria Lucarini; Ombretta Melaiu; Patrizia Tempora; Silvia D’Amico; Franco Locatelli; Doriana Fruci. Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment. Cancers 2021, 13, 433 .
AMA StyleValeria Lucarini, Ombretta Melaiu, Patrizia Tempora, Silvia D’Amico, Franco Locatelli, Doriana Fruci. Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment. Cancers. 2021; 13 (3):433.
Chicago/Turabian StyleValeria Lucarini; Ombretta Melaiu; Patrizia Tempora; Silvia D’Amico; Franco Locatelli; Doriana Fruci. 2021. "Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment." Cancers 13, no. 3: 433.
Interferon‐gamma (IFN‐γ) plays a key role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to a role in other conditions, including aplastic anemia (AA) and graft failure following allogeneic hematopoietic stem cell transplantation. Recently, the therapeutic potential of IFN‐γ inhibition has been documented; emapalumab, an anti‐IFN‐γ monoclonal antibody, has been approved in the United States for treatment of primary HLH that is refractory, recurrent or progressive, or in patients with intolerance to conventional therapy. Moreover, ruxolitinib, an inhibitor of JAK/STAT intracellular signaling, is currently being investigated for treating HLH. In AA, IFN‐γ inhibits hematopoiesis by disrupting the interaction between thrombopoietin and its receptor, c‐MPL. Eltrombopag, a small‐molecule agonist of c‐MPL, acts at a different binding site to IFN‐γ and is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate the role of IFN‐γ neutralization in secondary HLH and future studies could explore this strategy in controlling hyperinflammation due to CAR T cells.
Pietro Merli; Concetta Quintarelli; Luisa Strocchio; Franco Locatelli. The role of interferon‐gamma and its signaling pathway in pediatric hematological disorders. Pediatric Blood & Cancer 2021, 68, e28900 .
AMA StylePietro Merli, Concetta Quintarelli, Luisa Strocchio, Franco Locatelli. The role of interferon‐gamma and its signaling pathway in pediatric hematological disorders. Pediatric Blood & Cancer. 2021; 68 (4):e28900.
Chicago/Turabian StylePietro Merli; Concetta Quintarelli; Luisa Strocchio; Franco Locatelli. 2021. "The role of interferon‐gamma and its signaling pathway in pediatric hematological disorders." Pediatric Blood & Cancer 68, no. 4: e28900.
As the thymus represents the primary site of T-cell development, optimal thymic function is of paramount importance for the successful reconstitution of the adaptive immunity after allogeneic hematopoietic stem cell transplantation. Thymus involutes as part of the aging process and several factors, including previous chemotherapy treatments, conditioning regimen used in preparation to the allograft, occurrence of graft-versus-host disease, and steroid therapy that impair the integrity of the thymus, thus affecting its role in supporting T-cell neogenesis. Although the pathways governing its regeneration are still poorly understood, the thymus has a remarkable capacity to recover its function after damage. Measurement of both recent thymic emigrants and T-cell receptor excision circles is valuable tools to assess thymic output and gain insights on its function. In this review, we will extensively discuss available data on factors regulating thymic function after allogeneic hematopoietic stem cell transplantation, as well as the strategies and therapeutic approaches under investigation to promote thymic reconstitution and accelerate immune recovery in transplanted patients, including the use of cytokines, sex-steroid ablation, precursor T-cells, and thymus bioengineering. Although none of them is routinely used in the clinic, these approaches have the potential to enhance thymic function and immune recovery, not only in patients given an allograft but also in other conditions characterized by immune deficiencies related to a defective function of the thymus.
Enrico Velardi; Emmanuel Clave; Lucas C. M. Arruda; Francesca Benini; Franco Locatelli; Antoine Toubert. The role of the thymus in allogeneic bone marrow transplantation and the recovery of the peripheral T-cell compartment. Seminars in Immunopathology 2021, 43, 101 -117.
AMA StyleEnrico Velardi, Emmanuel Clave, Lucas C. M. Arruda, Francesca Benini, Franco Locatelli, Antoine Toubert. The role of the thymus in allogeneic bone marrow transplantation and the recovery of the peripheral T-cell compartment. Seminars in Immunopathology. 2021; 43 (1):101-117.
Chicago/Turabian StyleEnrico Velardi; Emmanuel Clave; Lucas C. M. Arruda; Francesca Benini; Franco Locatelli; Antoine Toubert. 2021. "The role of the thymus in allogeneic bone marrow transplantation and the recovery of the peripheral T-cell compartment." Seminars in Immunopathology 43, no. 1: 101-117.
Pietro Merli; Michael B. Jordan; Franco Locatelli. Possible roads to improve hemophagocytic lymphohistiocytosis outcome. Blood Advances 2020, 4, 6127 -6129.
AMA StylePietro Merli, Michael B. Jordan, Franco Locatelli. Possible roads to improve hemophagocytic lymphohistiocytosis outcome. Blood Advances. 2020; 4 (24):6127-6129.
Chicago/Turabian StylePietro Merli; Michael B. Jordan; Franco Locatelli. 2020. "Possible roads to improve hemophagocytic lymphohistiocytosis outcome." Blood Advances 4, no. 24: 6127-6129.
In this study, we explored whether Nutlin-3a, a well-known nontoxic small-molecule compound antagonizing the inhibitory interaction of MDM2 with the tumor suppressor p53, may restore ligands for natural killer (NK) cell-activating receptors (NK-ARs) on neuroblastoma (NB) cells to enhance the NK cell-mediated killing. NB cell lines were treated with Nutlin-3a, and the expression of ligands for NKG2D and DNAM-1 NK-ARs and the NB susceptibility to NK cells were evaluated. Adoptive transfer of human NK cells in a xenograft NB-bearing NSG murine model was assessed. Two datasets of NB patients were explored to correlate p53 expression with ligand expression. Luciferase assays and chromatin immunoprecipitation (ChIP) analysis of p53 functional binding on PVR promoter were performed. Primary NB cells were also treated with Nutlin-3a, and NB spheroids obtained from one high-risk patient were assayed for NK-cell cytotoxicity. We provide evidence showing that the Nutlin-3a-dependent rescue of p53 function in NB cells resulted in: (i) increased surface expression of ligands for NK-ARs, thus rendering NB cell lines significantly more susceptible to NK cell-mediated killing; (ii) shrinkage of human NB tumor masses that correlated with overall survival upon adoptive transfer of NK cells in NB-bearing mice; (iii) increased expression of ligands in primary NB cells and boosting of NK cell-mediated disaggregation of NB spheroids. We also found that p53 was a direct transcription factor regulating the expression of PVR ligand recognized by DNAM-1. Our findings demonstrated an immunomodulatory role of Nutlin-3a, which might be prospectively employed for a novel NK cell-based immunotherapy for NB.
Irene Veneziani; Paola Infante; Elisa Ferretti; Ombretta Melaiu; Cecilia Battistelli; Valeria Lucarini; Mirco Compagnone; Carmine Nicoletti; Aurora Castellano; Stefania Petrini; Marzia Ognibene; Annalisa Pezzolo; Lucia Di Marcotullio; Roberto Bei; Lorenzo Moretta; Vito Pistoia; Doriana Fruci; Vincenzo Barnaba; Franco Locatelli; Loredana Cifaldi. Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors. Cancer Immunology Research 2020, 9, 170 -183.
AMA StyleIrene Veneziani, Paola Infante, Elisa Ferretti, Ombretta Melaiu, Cecilia Battistelli, Valeria Lucarini, Mirco Compagnone, Carmine Nicoletti, Aurora Castellano, Stefania Petrini, Marzia Ognibene, Annalisa Pezzolo, Lucia Di Marcotullio, Roberto Bei, Lorenzo Moretta, Vito Pistoia, Doriana Fruci, Vincenzo Barnaba, Franco Locatelli, Loredana Cifaldi. Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors. Cancer Immunology Research. 2020; 9 (2):170-183.
Chicago/Turabian StyleIrene Veneziani; Paola Infante; Elisa Ferretti; Ombretta Melaiu; Cecilia Battistelli; Valeria Lucarini; Mirco Compagnone; Carmine Nicoletti; Aurora Castellano; Stefania Petrini; Marzia Ognibene; Annalisa Pezzolo; Lucia Di Marcotullio; Roberto Bei; Lorenzo Moretta; Vito Pistoia; Doriana Fruci; Vincenzo Barnaba; Franco Locatelli; Loredana Cifaldi. 2020. "Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors." Cancer Immunology Research 9, no. 2: 170-183.
Primary Hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening, hyperinflammatory disorder, characterized by uncontrolled activation of the immune system. Mutations affecting several genes coding for proteins involved in the cytotoxicity machinery of both natural killer (NK) and T cells have been found to be responsible for the development of pHLH. So far, front-line treatment, established on the results of large international trials, is based on the use of glucocorticoids, etoposide ± cyclosporine, followed by allogeneic hematopoietic stem cell transplantation (HSCT), the sole curative treatment for the genetic forms of the disease. However, despite major efforts to improve the outcome of pHLH, many patients still experience unfavorable outcomes, as well as severe toxicities; moreover, treatment-refractory or relapsing disease is a major challenge for pediatricians/hematologists. In this article, we review the epidemiology, etiology and pathophysiology of pHLH, with a particular focus on different cytokines at the origin of the disease. The central role of interferon-γ (IFNγ) in the development and maintenance of hyperinflammation is analyzed. The value of emapalumab, a novel IFNγ-neutralizing monoclonal antibody is discussed. Available data support the use of emapalumab for treatment of pHLH patients with refractory, recurrent or progressive disease, or intolerance to conventional therapy, recently, leading to FDA approval of the drug for these indications. Additional data are needed to define the role of emapalumab in front-line treatment or in combination with other drugs.
Pietro Merli; Mattia Algeri; Stefania Gaspari; Franco Locatelli. Novel Therapeutic Approaches to Familial HLH (Emapalumab in FHL). Frontiers in Immunology 2020, 11, 1 .
AMA StylePietro Merli, Mattia Algeri, Stefania Gaspari, Franco Locatelli. Novel Therapeutic Approaches to Familial HLH (Emapalumab in FHL). Frontiers in Immunology. 2020; 11 ():1.
Chicago/Turabian StylePietro Merli; Mattia Algeri; Stefania Gaspari; Franco Locatelli. 2020. "Novel Therapeutic Approaches to Familial HLH (Emapalumab in FHL)." Frontiers in Immunology 11, no. : 1.
Down syndrome (DS) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans, which results from the triplication of chromosome 21. To search for biomarkers for the early detection and exploration of the disease mechanisms, here, we investigated the protein expression signature of peripheral blood mononuclear cells (PBMCs) in DS children compared with healthy donors (HD) by using an in-depth label-free shotgun proteomics approach. Identified proteins are found associated with metabolic pathways, cellular trafficking, DNA structure, stress response, cytoskeleton network, and signaling pathways. The results showed that a well-defined number of dysregulated pathways retain a prominent role in mediating DS pathological features. Further, proteomics results are consistent with published study in DS and provide evidences that increased oxidative stress and the increased induction of stress related response, is a participant in DS pathology. In addition, the expression levels of some key proteins have been validated by Western blot analysis while protein carbonylation, as marker of protein oxidation, was investigated. The results of this study propose that PBMCs from DS children might be in an activated state where endoplasmic reticulum stress and increased production of radical species are one of the primary events contributing to multiple DS pathological features.
Chiara Lanzillotta; Viviana Greco; Diletta Valentini; Alberto Villani; Valentina Folgiero; Matteo Caforio; Franco Locatelli; Sara Pagnotta; Eugenio Barone; Andrea Urbani; Fabio Di Domenico; Marzia Perluigi. Proteomics Study of Peripheral Blood Mononuclear Cells in Down Syndrome Children. Antioxidants 2020, 9, 1112 .
AMA StyleChiara Lanzillotta, Viviana Greco, Diletta Valentini, Alberto Villani, Valentina Folgiero, Matteo Caforio, Franco Locatelli, Sara Pagnotta, Eugenio Barone, Andrea Urbani, Fabio Di Domenico, Marzia Perluigi. Proteomics Study of Peripheral Blood Mononuclear Cells in Down Syndrome Children. Antioxidants. 2020; 9 (11):1112.
Chicago/Turabian StyleChiara Lanzillotta; Viviana Greco; Diletta Valentini; Alberto Villani; Valentina Folgiero; Matteo Caforio; Franco Locatelli; Sara Pagnotta; Eugenio Barone; Andrea Urbani; Fabio Di Domenico; Marzia Perluigi. 2020. "Proteomics Study of Peripheral Blood Mononuclear Cells in Down Syndrome Children." Antioxidants 9, no. 11: 1112.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of children and adolescents. The fusion-positive (FP)-RMS variant expressing chimeric oncoproteins such as PAX3-FOXO1 and PAX7-FOXO1 is at high risk. The fusion negative subgroup, FN-RMS, has a good prognosis when non-metastatic. Despite a multimodal therapeutic approach, FP-RMS and metastatic FN-RMS often show a dismal prognosis with 5-year survival of less than 30%. Therefore, novel targets need to be discovered to develop therapies that halt tumor progression, reducing long-term side effects in young patients. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that regulates focal contacts at the cellular edges. It plays a role in cell motility, survival, and proliferation in response to integrin and growth factor receptors’ activation. FAK is often dysregulated in cancer, being upregulated and/or overactivated in several adult and pediatric tumor types. In RMS, both in vitro and preclinical studies point to a role of FAK in tumor cell motility/invasion and proliferation, which is inhibited by FAK inhibitors. In this review, we summarize the data on FAK expression and modulation in RMS. Moreover, we give an overview of the approaches to inhibit FAK in both preclinical and clinical cancer settings.
Clara Perrone; Silvia Pomella; Matteo Cassandri; Maria Rita Braghini; Michele Pezzella; Franco Locatelli; Rossella Rota. FAK Signaling in Rhabdomyosarcoma. International Journal of Molecular Sciences 2020, 21, 8422 .
AMA StyleClara Perrone, Silvia Pomella, Matteo Cassandri, Maria Rita Braghini, Michele Pezzella, Franco Locatelli, Rossella Rota. FAK Signaling in Rhabdomyosarcoma. International Journal of Molecular Sciences. 2020; 21 (22):8422.
Chicago/Turabian StyleClara Perrone; Silvia Pomella; Matteo Cassandri; Maria Rita Braghini; Michele Pezzella; Franco Locatelli; Rossella Rota. 2020. "FAK Signaling in Rhabdomyosarcoma." International Journal of Molecular Sciences 21, no. 22: 8422.
Giuseppe Ippolito; Francesco Nicola Lauria; Franco Locatelli; Nicola Magrini; Chiara Montaldo; Raffaella Sadun; Markus Maeurer; Gino Strada; Francesco Vairo; Salvatore Curiale; Antoine Lafont; Antonino di Caro; Maria Rosaria Capobianchi; Rainer Meilicke; Eskild Petersen; Alimuddin Zumla; Michel Pletschette. Lessons from the COVID-19 Pandemic—Unique Opportunities for Unifying, Revamping and Reshaping Epidemic Preparedness of Europe’s Public Health Systems. International Journal of Infectious Diseases 2020, 101, 361 -366.
AMA StyleGiuseppe Ippolito, Francesco Nicola Lauria, Franco Locatelli, Nicola Magrini, Chiara Montaldo, Raffaella Sadun, Markus Maeurer, Gino Strada, Francesco Vairo, Salvatore Curiale, Antoine Lafont, Antonino di Caro, Maria Rosaria Capobianchi, Rainer Meilicke, Eskild Petersen, Alimuddin Zumla, Michel Pletschette. Lessons from the COVID-19 Pandemic—Unique Opportunities for Unifying, Revamping and Reshaping Epidemic Preparedness of Europe’s Public Health Systems. International Journal of Infectious Diseases. 2020; 101 ():361-366.
Chicago/Turabian StyleGiuseppe Ippolito; Francesco Nicola Lauria; Franco Locatelli; Nicola Magrini; Chiara Montaldo; Raffaella Sadun; Markus Maeurer; Gino Strada; Francesco Vairo; Salvatore Curiale; Antoine Lafont; Antonino di Caro; Maria Rosaria Capobianchi; Rainer Meilicke; Eskild Petersen; Alimuddin Zumla; Michel Pletschette. 2020. "Lessons from the COVID-19 Pandemic—Unique Opportunities for Unifying, Revamping and Reshaping Epidemic Preparedness of Europe’s Public Health Systems." International Journal of Infectious Diseases 101, no. : 361-366.
Background: RT-PCR on nasopharyngeal (NPS)/oropharyngeal swabs is the gold standard for diagnosis of SARS-CoV-2 infection and viral load monitoring. Oral fluid (OF) is an alternate clinical sample, easy and safer to collect and could be useful for COVID-19 diagnosis, monitoring viral load and shedding. Methods: Optimal assay conditions and analytical sensitivity were established for the commercial Simplexa™ COVID-19 Direct assay adapted to OF matrix. The assay was used to test 337 OF and NPS specimens collected in parallel from 164 hospitalized patients; 50 bronchoalveolar lavage (BAL) specimens from a subgroup of severe COVID-19 cases were also analysed. Results: Using Simplexa™ COVID-19 Direct on OF matrix, 100% analytical detection down to 1 TCID50/mL (corresponding to 4 × 103 copies (cp)/mL) was observed. No crossreaction with other viruses transmitted through the respiratory toute was observed. Parallel testing of 337 OF and NPS samples showed highly concordant results (κ = 0.831; 95 % CI = 0.771–0.891), and high correlation of Ct values (r = 0.921; p < 0.0001). High concordance and elevated correlation was observed also between OF and BAL. Prolonged viral RNA shedding was observed up to 100 days from symptoms onset (DSO), with 32% and 29% positivity observed in OF and NPS samples, respectively, collected between 60 and 100 DSO. Conclusions: Simplexa™ COVID-19 Direct assays on OF have high sensitivity and specificity to detect SARS-CoV-2 RNA and provide an alternative to NPS for diagnosis and monitoring SARS-CoV-2 shedding.
Licia Bordi; Giuseppe Sberna; Eleonora Lalle; Pierluca Piselli; Francesca Colavita; Emanuele Nicastri; Andrea Antinori; Evangelo Boumis; Nicola Petrosillo; Luisa Marchioni; Giulia Minnucci; Elena D’Agostini; Concetta Castilletti; Franco Locatelli; Alimuddin Zumla; Giuseppe Ippolito; Maria Capobianchi; on behalf of INMI ReCOVeRI Study Group. Frequency and Duration of SARS-CoV-2 Shedding in Oral Fluid Samples Assessed by a Modified Commercial Rapid Molecular Assay. Viruses 2020, 12, 1184 .
AMA StyleLicia Bordi, Giuseppe Sberna, Eleonora Lalle, Pierluca Piselli, Francesca Colavita, Emanuele Nicastri, Andrea Antinori, Evangelo Boumis, Nicola Petrosillo, Luisa Marchioni, Giulia Minnucci, Elena D’Agostini, Concetta Castilletti, Franco Locatelli, Alimuddin Zumla, Giuseppe Ippolito, Maria Capobianchi, on behalf of INMI ReCOVeRI Study Group. Frequency and Duration of SARS-CoV-2 Shedding in Oral Fluid Samples Assessed by a Modified Commercial Rapid Molecular Assay. Viruses. 2020; 12 (10):1184.
Chicago/Turabian StyleLicia Bordi; Giuseppe Sberna; Eleonora Lalle; Pierluca Piselli; Francesca Colavita; Emanuele Nicastri; Andrea Antinori; Evangelo Boumis; Nicola Petrosillo; Luisa Marchioni; Giulia Minnucci; Elena D’Agostini; Concetta Castilletti; Franco Locatelli; Alimuddin Zumla; Giuseppe Ippolito; Maria Capobianchi; on behalf of INMI ReCOVeRI Study Group. 2020. "Frequency and Duration of SARS-CoV-2 Shedding in Oral Fluid Samples Assessed by a Modified Commercial Rapid Molecular Assay." Viruses 12, no. 10: 1184.
Background: Adenosine to inosine (A-to-I) RNA editing is the most frequent editing event in humans. It converts adenosine to inosine in double-stranded RNA regions (in coding and non-coding RNAs) through the action of the adenosine deaminase acting on RNA (ADAR) enzymes. Long non-coding RNAs, particularly abundant in the brain, account for a large fraction of the human transcriptome, and their important regulatory role is becoming progressively evident in both normal and transformed cells. Results: Herein, we present a bioinformatic analysis to generate a comprehensive inosinome picture in long non-coding RNAs (lncRNAs), using an ad hoc index and searching for de novo editing events in the normal brain cortex as well as in glioblastoma, a highly aggressive human brain cancer. We discovered >10,000 new sites and 335 novel lncRNAs that undergo editing, never reported before. We found a generalized downregulation of editing at multiple lncRNA sites in glioblastoma samples when compared to the normal brain cortex. Conclusion: Overall, our study discloses a novel layer of complexity that controls lncRNAs in the brain and brain cancer.
Domenico Alessandro Silvestris; Chiara Scopa; Sara Hanchi; Franco Locatelli; Angela Gallo. De Novo A-to-I RNA Editing Discovery in lncRNA. Cancers 2020, 12, 2959 .
AMA StyleDomenico Alessandro Silvestris, Chiara Scopa, Sara Hanchi, Franco Locatelli, Angela Gallo. De Novo A-to-I RNA Editing Discovery in lncRNA. Cancers. 2020; 12 (10):2959.
Chicago/Turabian StyleDomenico Alessandro Silvestris; Chiara Scopa; Sara Hanchi; Franco Locatelli; Angela Gallo. 2020. "De Novo A-to-I RNA Editing Discovery in lncRNA." Cancers 12, no. 10: 2959.
Myelodysplastic syndromes (MDS) are hematopoietic disorders rare in childhood, often occurring in patients with inherited bone marrow failure syndromes or germinal predisposition syndromes. Among the latter, one of the most frequent involves the gene GATA binding protein 2 (GATA2), coding for a transcriptional regulator of hematopoiesis. The genetic lesion as well as the clinical phenotype are extremely variable; many patients present hematological malignancies, especially MDS with the possibility to evolve into acute myeloid leukemia. Variable immune dysfunction, especially resulting in B- and NK-cell lymphopenia, lead to severe infections, including generalized warts and mycobacterial infection. Defects of alveolar macrophages lead to pulmonary alveolar proteinosis through inadequate clearance of surfactant proteins. Currently, there are no clear guidelines for the monitoring and treatment of patients with GATA2 mutations. In patients with MDS, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT) that restores normal hematopoiesis preventing the progression to acute myeloid leukemia and clears long-standing infections. However, to date, the donor type, conditioning regimen, and the optimal time to proceed to HSCT, as well as the level of chimerism needed to reverse the phenotype, remain unclear highlighting the need for consensus guidelines.
Antonella Bruzzese; Davide Leardini; Riccardo Masetti; Luisa Strocchio; Katia Girardi; Mattia Algeri; Giada Del Baldo; Franco Locatelli; Angela Mastronuzzi. GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes. Cancers 2020, 12, 2962 .
AMA StyleAntonella Bruzzese, Davide Leardini, Riccardo Masetti, Luisa Strocchio, Katia Girardi, Mattia Algeri, Giada Del Baldo, Franco Locatelli, Angela Mastronuzzi. GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes. Cancers. 2020; 12 (10):2962.
Chicago/Turabian StyleAntonella Bruzzese; Davide Leardini; Riccardo Masetti; Luisa Strocchio; Katia Girardi; Mattia Algeri; Giada Del Baldo; Franco Locatelli; Angela Mastronuzzi. 2020. "GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes." Cancers 12, no. 10: 2962.
Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches.
Giacomo Milletti; Luisa Strocchio; Daria Pagliara; Katia Girardi; Roberto Carta; Angela Mastronuzzi; Franco Locatelli; Francesca Nazio. Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition. Cancers 2020, 12, 2684 .
AMA StyleGiacomo Milletti, Luisa Strocchio, Daria Pagliara, Katia Girardi, Roberto Carta, Angela Mastronuzzi, Franco Locatelli, Francesca Nazio. Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition. Cancers. 2020; 12 (9):2684.
Chicago/Turabian StyleGiacomo Milletti; Luisa Strocchio; Daria Pagliara; Katia Girardi; Roberto Carta; Angela Mastronuzzi; Franco Locatelli; Francesca Nazio. 2020. "Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition." Cancers 12, no. 9: 2684.