Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.     

Dispersive optical solitons by the semi-inverse variational principle

In this paper an analytical expression for an optical soliton is obtained with the aid of He's semi-inverse variational principle in the presence of third- and fourth-order dispersion as well as inter-modal dispersion. Three laws of nonlinear media are considered in this paper: the Kerr law, the power law and the log law.     

Modulatory Effects of Polyphenols on Apoptosis Induction: Relevance for Cancer Prevention

Polyphenols, occurring in fruit and vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products, have been demonstrated to have clear antioxidant properties in vitro, and many of their biological actions have been attributed to their intrinsic reducing capabilities. However, it has become clear that, in complex biological systems, polyphenols exhibit several additional properties which are yet poorly understood. Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for the normal embryonic development and for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary role in various pathological processes, since too little or too much apoptosis can lead to proliferative or degenerative diseases, respectively. Cancer cells are characterized by a deregulated proliferation, and/or an inability to undergo programmed cell death. A large body of evidence indicates that polyphenols can exert chemopreventive effects towards different organ specific cancers, affecting the overall process of carcinogenesis by several mechanisms: inhibition of DNA synthesis, modulation of ROS production, regulation of cell cycle arrest, modulation of survival/proliferation pathways. In addition, polyphenols can directly influence different points of the apoptotic process, and/or the expression of regulatory proteins. Although the bulk of data has been obtained in in vitro systems, a number of clinical studies suggesting a preventive and therapeutic effectiveness of polyphenols in vivo is available. However, a deeper knowledge of the underlying mechanisms responsible for the modulation of apoptosis by polyphenols, and their real effectiveness, is necessary in order to propose them as potential chemopreventive and chemotherapeutic candidates for cancer treatment.     

Bioaccessibility of provitamin A carotenoids in bananas (Musa spp.) and derived dishes in African countries

Bananas and plantains (Musa spp.) constitute an important component of the diet in Africa. Substantial levels of provitamin A carotenoids (pVACs) in Musa fruit have been reported, but the bioaccessibility of these pVACs remains unknown. In this study, we used an in vitro digestion model to assess the bioaccessibility (i.e. the transfer into micelles) of pVACs from boiled bananas and derived dishes using the Eastern Democratic Republic of Congo as a study context. In particular, the effect of different food ingredients added to boiled bananas on pVAC’s bioaccessibility was studied. The bioaccessibility of all-trans β-carotene ranged from 10% to 32%, depending on the food recipes, and was modified, particularly when pVACs-rich ingredients (palm oil/amaranth) were added. Efficiency of micellarization of all-trans β-carotene was similar to that of all-trans α-carotene and depended on the cultivar (Musilongo, plantain type, 16%; Vulambya, East African cooking type, 28%), while that of the 13-cis isomer was higher (21–33.5%). Taking into account bioaccessibility, the estimated vitamin A activity was significantly different across the different Musa-based dishes tested. Results are discussed in terms of recommendations to help reduce vitamin A deficiency in Musa-dependent African communities.     

Effects of paternal and maternal depressive symptoms on child internalizing symptoms and asthma disease activity: Mediation by interparental negativity and parenting.

This study tested a hypothesized model of the relationships among parental depressive symptoms, family process (interparental negativity and negative parenting behavior), child internalizing symptoms, and asthma disease activity. A total of 106 children with asthma, aged 7 to 17, participated with their fathers and mothers. Parental depressive symptoms were assessed by self-report. Interparental and parenting behaviors were observed and rated during family discussion tasks. Child internalizing symptoms were assessed by self-report and by clinician interview and rating. Asthma disease activity was assessed according to National Heart, Lung and Blood Institute guidelines. Results of structural equation modeling generally supported interparental negativity and negative parenting behavior as mediators linking parental depressive symptoms and child emotional and physical dysfunction. However, paternal and maternal depressive symptoms play their role through different pathways of negative family process. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

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.     

Application of ESI and MALDI‐TOF MS for triacylglycerols analysis in edible oils

Triacylglycerols (TAG) are the most important group of compounds present in vegetable oils. These biomolecules, determining the physical, chemical and nutritional properties of the oils, are considered to be good fingerprints for quality and authenticity control. Therefore, TAGs characterization is a very important task in edible oil field, which has been undertaken by different analytical methods. The analysis of vegetable oils is still dominated by classic determinations, which are however laborious and time‐consuming and cannot be used routinely. More recently, advances in MS instrumentations coupled with online separation techniques and data processing have contributed to great expansion of MS in oil study, allowing the development of innovative analytical approaches that exhibit higher sensitivity, accuracy and rapidity in vegetable oils investigations. In the present contribution, a review of the most relevant applications of novel mass spectrometric techniques, such as ESI and MALDI, both alone and hyphenated with HPLC, used for analysis of the complex TAGs mixture of edible oils is illustrated.     

Design,Synthesis, and Evaluation of WC5 Analogues as Inhibitors of Human Cytomegalovirus Immediate‐Early 2 Protein,a Promising Target for Anti‐HCMV Treatment

Although human cytomegalovirus (HCMV) infection is mostly asymptomatic for immunocompetent individuals, it remains a serious threat for those who are immunocompromised, in whom it is associated with various clinical manifestations. The therapeutic utility of the few available anti‐HCMV drugs is limited by several drawbacks, including cross‐resistance due to their common mechanism of action, i.e., inhibition of viral DNA polymerase. Therefore, compounds that target other essential viral events could overcome this problem. One example of this is the 6‐aminoquinolone WC5 , which acts by directly blocking the transactivation of essential viral Early genes by the Immediate‐Early 2 (IE2) protein. In this study, the quinolone scaffold of the lead compound WC5 was investigated in depth, defining more suitable substituents for each of the scaffold positions explored and identifying novel, potent and nontoxic compounds. Some compounds showed potent anti‐HCMV activity by interfering with IE2‐dependent viral E gene expression. Among them, naphthyridone 1 was also endowed with potent anti‐HIV activity in latently infected cells. Their antiviral profile along with their innovative mechanism of action make these anti‐HCMV quinolones a very promising class of compounds to be exploited for more effective antiviral therapeutic treatment.