The challenge of detecting intracluster filaments with Faraday Rotation

The detection of filaments in the cosmic web will be crucial to distinguish between the possible magnetogenesis scenarios and future large polarization surveys will be able to shed light on their magnetization level. In this work, we use numerical simulations of galaxy clusters to investigate their possible detection. We compute the Faraday Rotation signal in intracluster filaments and compare it to its surrounding environment. We find that the expected big improvement in sensitivity with the SKA-MID will in principle allow the detection of a large fraction of filaments surrounding galaxy clusters. However, the contamination of the intrinsic Faraday Rotation of background polarized sources will represent a big limiter to the number of objects that can be significantly detected. We discuss possible strategies to minimize this effect and increase the chances of detection of the cosmic web with the large statistics expected from future surveys.Comment: 16 pages, accepted to Galaxie

The role of interferon‐gamma and its signaling pathway in pediatric hematological disorders

AbstractInterferon‐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

Targeting Multiple-Myeloma-Induced Immune Dysfunction to Improve Immunotherapy Outcomes

Multiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC) dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients' clinical outcome

Numb Isoforms Deregulation in Medulloblastoma and Role of p66 Isoform in Cancer and Neural Stem Cells

Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance

Transplantation and innate immunity: the lesson of natural killer cells

Natural killer cells have been demonstrated to play a major role in mediating an anti-leukemia effect in patients given a T-cell depleted allogeneic hematopoietic stem cell transplantation from an HLA-haploidentical family donor. In particular, donor-derived natural killer cells, which are alloreactive (i.e. KIR/HLA mismatched) towards recipient cells, significantly contribute to the eradication of leukemia blasts escaping the preparative regimen to transplantation. A recent study on high-risk pediatric acute lymphoblastic leukemia refractory to chemotherapy further highlighted the importance of donors with alloreactive natural killer cells in haploidentical hematopoietic stem cell transplantation, as it demonstrated that these cells can emerge starting from the fourth-fifth month after the allograft and persist for many months. This study represents a major breakthrough in the cure of otherwise fatal leukemias, providing information on the best criteria for choosing the optimal donor

Multidrug resistance and cancer stem cells in neuroblastoma and hepatoblastoma

Chemotherapy is one of the major modalities in treating cancers. However, its effectiveness is limited by the acquisition of multidrug resistance (MDR). Several mechanisms could explain the up-regulation of MDR genes/proteins in cancer after chemotherapy. It is known that cancer stem cells (CSCs) play a role as master regulators. Therefore, understanding the mechanisms that regulate some traits of CSCs may help design efficient strategies to overcome chemoresistance. Different CSC phenotypes have been identified, including those found in some pediatric malignancies. As solid tumors in children significantly differ from those observed in adults, this review aims at providing an overview of the mechanistic relationship between MDR and CSCs in common solid tumors, and, in particular, focuses on clinical as well as experimental evidence of the relations between CSCs and MDR in neuroblastoma and hepatoblastoma. Finally, some novel approaches, such as concomitant targeting of multiple key transcription factors governing the stemness of CSCs, as well as nanoparticle-based approaches will also be briefly addressed

Human NK cells: from surface receptors to the therapy of leukemias and solid tumors

Natural Killer (NK) cells are major effector cells of the innate immunity. The discovery, over two decades ago, of major histocompatibility complex-class l-specific inhibitory NK receptors and subsequently of activating receptors, recognizing ligands expressed by tumor or virus-infected cells, paved the way to our understanding of the mechanisms of selective recognition and killing of tumor cells. Although NK cells can efficiently kill tumor cells of different histotypes in vitro, their activity may be limited in vivo by their inefficient trafficking to tumor lesions and by the inhibition of their function induced by tumor cells themselves and by the tumor microenvironment. On the other hand, the important role of NK cells has been clearly demonstrated in the therapy of high risk leukemias in the haploidentical hematopoietic stem cell (HSC) transplantation setting. NK cells derived from donor HSC kill leukemic cells residual after the conditioning regimen, thus preventing leukemia relapses. In addition, they also kill residual dendritic cells and T lymphocytes, thus preventing both GvH disease and graft rejection

Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in patients with thalassaemia major

The safety and efficacy of a preparation with treosulfan/thiotepa/fludarabine were explored in 20 thalassaemia patients given allogeneic marrow transplantation. Seventeen patients were transplanted from unrelated donors after receiving anti-thymocyte globulin. The regimen was well tolerated. Two patients experienced secondary graft failure; one died of acute graft-versus-host disease. Cumulative incidence (95% confidence interval, CI) of transplantation-related mortality and graft failure was 5% (95% CI, 0-34%) and 11% (95% CI, 3-43%), respectively. Two-year probability of survival and thalassaemia-free survival was 95% (95% CI, 85-100%) and 85% (95% CI, 66-100%), respectively. This regimen might find elective application in patients at high risk of developing life-threatening complications

IRF1 and NF-kB restore MHC class I-restricted tumor antigen processing and presentation to cytotoxic T cells in aggressive neuroblastoma

Neuroblastoma (NB), the most common solid extracranial cancer of childhood, displays a remarkable low expression of Major Histocompatibility Complex class I (MHC-I) and Antigen Processing Machinery (APM) molecules, including Endoplasmic Reticulum (ER) Aminopeptidases, and poorly presents tumor antigens to Cytotoxic T Lymphocytes (CTL). We have previously shown that this is due to low expression of the transcription factor NF-kB p65. Herein, we show that not only NF-kB p65, but also the Interferon Regulatory Factor 1 (IRF1) and certain APM components are low in a subset of NB cell lines with aggressive features. Whereas single transfection with either IRF1, or NF-kB p65 is ineffective, co-transfection results in strong synergy and substantial reversion of the MHC-I/APM-low phenotype in all NB cell lines tested. Accordingly, linked immunohistochemistry expression patterns between nuclear IRF1 and p65 on the one hand, and MHC-I on the other hand, were observed in vivo. Absence and presence of the three molecules neatly segregated between high-grade and low-grade NB, respectively. Finally, APM reconstitution by double IRF1/p65 transfection rendered a NB cell line susceptible to killing by anti MAGE-A3 CTLs, lytic efficiency comparable to those seen upon IFN-gamma treatment. This is the first demonstration that a complex immune escape phenotype can be rescued by reconstitution of a limited number of master regulatory genes. These findings provide molecular insight into defective MHC-I expression in NB cells and provide the rational for T cell-based immunotherapy in NB variants refractory to conventional therapy

Targeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomes

Multiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC) dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients' clinical outcome