Potential Role of Sirtuin as a Therapeutic Target for Neurodegenerative Diseases

The sirtuins (SIRTs) are protein-modifying enzymes that are distributed ubiquitously in all organisms. SIRT1 is a mammalian homologue of yeast nicotinamide-adenine-dinucleotide-dependent deacetylase silent information regulator 2 (known as Sir2), which is the best-characterized SIRT family member. It regulates longevity in several model organisms and is involved in several processes in mammalian cells including cell survival, differentiation, and metabolism. SIRT1 induction, either by SIRT-activating compounds such as resveratrol, or metabolic conditioning associated with caloric restriction, could have neuroprotective qualities and thus delay the neurodegenerative process, thereby promoting longevity. However, the precise mechanistic liaison between the activation of SIRT and extended healthy aging or delaying age-related diseases in humans has yet to be established

Lessons, Challenges and Future Therapeutic Opportunities for PI3K Inhibition in CLL

Chronic lymphocytic leukemia (CLL) shows constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of the B-cell receptor (BCR) signaling. PI3K inhibitors have been evaluated in CLL therapy, bringing a new treatment opportunity for patients with this disease. Despite the proven therapeutic efficacy, the use of approved PI3K inhibitors is limited by severe immune-mediated toxicities and given the availability of other more tolerable agents. This article reviews the relevance of PI3K signaling and pharmacologic inhibition in CLL. Data on efficacy and toxicity of PI3K inhibitors are also presented, as well as strategies for overcoming barriers for their clinical use in CLL treatment

NK Cells in Chronic Lymphocytic Leukemia and Their Therapeutic Implications

Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. Several immune effectors are impaired in CLL, including T and natural killer (NK) cells. The role of T cells in defense against CLL and in CLL progression and immunotherapy has been extensively studied. Less is known about the role of NK cells in this leukemia, and data on NK cell alterations in CLL are contrasting. Besides studies showing that NK cells have intrinsic defects in CLL, there is a large body of evidence indicating that NK cell dysfunctions in CLL mainly depend on the escape mechanisms employed by leukemic cells. In keeping, it has been shown that NK cell functions, including antibody-dependent cellular cytotoxicity (ADCC), can be retained and/or restored after adequate stimulation. Therefore, due to their preserved ADCC function and the reversibility of CLL-related dysfunctions, NK cells are an attractive source for novel immunotherapeutic strategies in this disease, including chimeric antigen receptor (CAR) therapy. Recently, satisfying clinical responses have been obtained in CLL patients using cord blood-derived CAR-NK cells, opening new possibilities for further exploring NK cells in the immunotherapy of CLL. However, notwithstanding the promising results of this clinical trial, more evidence is needed to fully understand whether and in which CLL cases NK cell-based immunotherapy may represent a valid, alternative/additional therapeutic option for this leukemia. In this review, we provide an overview of the current knowledge about phenotypic and functional alterations of NK cells in CLL and the mechanisms by which CLL cells circumvent NK cell-mediated immunosurveillance. Additionally, we discuss the potential relevance of using NK cells in CLL immunotherapy

Prognostic Impact and Risk Factors of Infections in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

none31nononeMauro, Francesca Romana; Giannarelli, Diana; Visentin, Andrea; Reda, Gianluigi; Sportoletti, Paolo; Frustaci, Anna Maria; Chiarenza, Annalisa; Ciolli, Stefania; Vitale, Candida; Laurenti, Luca; De Paoli, Lorenzo; Murru, Roberta; Gentile, Massimo; Rigolin, Gian Matteo; Levato, Luciano; Giordano, Annamaria; Del Poeta, Giovanni; Stelitano, Caterina; Ielo, Claudia; Noto, Alessandro; Guarente, Valerio; Molica, Stefano; Coscia, Marta; Tedeschi, Alessandra; Gaidano, Gianluca; Cuneo, Antonio; Foà, Robin; Martelli, Maurizio; Girmenia, Corrado; Gentile, Giuseppe; Trentin, LivioMauro, Francesca Romana; Giannarelli, Diana; Visentin, Andrea; Reda, Gianluigi; Sportoletti, Paolo; Frustaci, Anna Maria; Chiarenza, Annalisa; Ciolli, Stefania; Vitale, Candida; Laurenti, Luca; De Paoli, Lorenzo; Murru, Roberta; Gentile, Massimo; Rigolin, Gian Matteo; Levato, Luciano; Giordano, Annamaria; Del Poeta, Giovanni; Stelitano, Caterina; Ielo, Claudia; Noto, Alessandro; Guarente, Valerio; Molica, Stefano; Coscia, Marta; Tedeschi, Alessandra; Gaidano, Gianluca; Cuneo, Antonio; Foà, Robin; Martelli, Maurizio; Girmenia, Corrado; Gentile, Giuseppe; Trentin, Livi

Prediction of outcomes in cll patients treated with ibrutinib: validation of current prognostic models and development of a simplified three-factor model

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