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Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is an example of hematological disease where cooperation between genetic defects and tumor microenvironmental interaction is involved in pathogenesis. CLL is a disease that is considered as “addicted to the host”; indeed, the crosstalk between leukemic cells and the tumor microenvironment is essential for leukemic clone maintenance supporting CLL cells’ survival, proliferation, and protection from drug-induced apoptosis. CLL cells are not innocent bystanders but actively model and manipulate the surrounding microenvironment to their own advantage. Besides the different players involved in this crosstalk, nurse-like cells (NLC) resemble features related to leukemia-associated macrophages with an important function in preserving CLL cell survival and supporting an immunosuppressive microenvironment. This review provides a comprehensive overview of the role played by NLC in creating a nurturing and permissive milieu for CLL cells, illustrating the therapeutic possibilities in order to specifically target and re-educate them.

Interferon regulatory factor 4 (IRF4) is a transcriptional regulator of immune system development and function. Here, we investigated the role of IRF4 in controlling responsiveness to B-cell receptor (BCR) stimulation in chronic lymphocytic leukemia (CLL). We modulated IRF4 levels by transfecting CLL cells with an IRF4 vector or by silencing using small-interfering RNAs. Higher IRF4 levels attenuated BCR signaling by reducing AKT and ERK phosphorylation and calcium release. Conversely, IRF4 reduction improved the strength of the intracellular cascade activated by BCR engagement. Our results also indicated that IRF4 negatively regulates the expression of the spleen tyrosine kinase SYK, a crucial protein for propagation of BCR signaling, and the zinc finger DNA-binding protein IKAROS. We modulated IKAROS protein levels both by genetic manipulation and pharmacologically by treating CLL cells with lenalidomide and avadomide (IMIDs). IKAROS promoted BCR signaling by reducing the expression of inositol 5-phosphatase SHIP1. Lastly, IMIDs induced IRF4 expression, while down-regulating IKAROS and interfered with survival advantage mediated by BCR triggering, also in combination with ibrutinib. Overall, our findings elucidate the mechanism by which IRF4 tunes BCR signaling in CLL cells. Low IRF4 levels allow an efficient transmission of BCR signal throughout the accumulation of SYK and IKAROS.

Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta] = 9.8 · 10-5, PMeta = 1.5 · 10-4, and PMeta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P = 2.46 · 10-7) and primary monocytes (P = 4.31 · 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development. ispartof: INFECTION AND IMMUNITY vol:88 issue:4 ispartof: location:United States status: published

Best practices are, by definition, the best ways to reach a specific goal. In the environmental field, best practices are experiences and quality projects carried out in the territory, by institutions, companies or citizens, that produce benefits in different environmental sectors applied to solve a concrete problem. Relevant features of best practices are their validation and replicability in time and space. In the context of the EU Co-funded BIG (Improve governance, management and sustainable valorization of coastal and rural protected areas and contributing to the implementation of the Natura 2000 provisions in Greece and Italy) best practices have been collected through a web search and questionnaires submitted to the managers of the protected areas to build a reference database/atlas. The database critical analysis has highlighted some gaps about the effective presence and applicability of these best practices. Moreover, their effectiveness has been analyzed on the base of the specific characteristics of the Italian and Greek areas involved in the BIG project. Some contrasting problems to the best practice definition have been highlighted.

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Correct definition of the level of risk of invasive fungal infections is the first step in improving the targeting of preventive strategies. We investigated the potential relationship between pre-hospitalization exposure to sources of fungi and the development of invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia after their first course of chemotherapy. From January 2010 to April 2012, all consecutive acute myeloid leukemia patients in 33 Italian centers were prospectively registered. Upon first admission, information about possible pre-chemotherapy risk factors and environmental exposure was collected. We recorded data regarding comorbid conditions, employment, hygienic habits, working and living environment, personal habits, hobbies, and pets. All invasive fungal infections occurring within 30 days after the first course of chemotherapy were recorded. Of the 1,192 patients enrolled in this study, 881 received intensive chemotherapy and were included in the present analysis. Of these, 214 developed an invasive fungal infection, including 77 proven/probable cases (8.7%). Of these 77 cases, 54 were proven/probable invasive mold infections (6.1%) and 23 were proven yeast infections (2.6%). Upon univariate analysis, a significant association was found between invasive mold infections and age, performance status, diabetes, chronic obstructive pulmonary disease, smoking, cocaine use, job, hobbies, and a recent house renovation. Higher body weight resulted in a reduced risk of invasive mold infections. Multivariate analysis confirmed the role of performance status, job, body weight, chronic obstructive pulmonary disease, and house renovation. In conclusion, several hospital-independent variables could potentially influence the onset of invasive mold infections in patients with acute myeloid leukemia. Investigation of these factors upon first admission may help to define a patient's risk category and improve targeted prophylactic strategies. (Clinicaltrial.gov: NCT01315925)

Recent studies suggest that immune-modulating single nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of Invasive Aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4Rrs2107356 and IL8rs2227307 SNPs were associated with an increased risk of IA (OR=1.92, 95%CI: 1.20-3.09 and OR=1.73, 1.06-2.81) whereas the IL12Brs3212227 and IFN?rs2069705 variants were significantly associated with a decreased risk of developing the infection (OR=0.60, 0.38-0.96 and OR=0.63, 0.41-0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFN?rs2069705 SNPs was stronger in allo-HSCT (OR=5.63, 1.20-3.09 and OR=0.24, 0.10-0.59) than in non-HSCT patients, suggesting that the presence of these SNPs may render patients more vulnerable to infection especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFN?rs2069705C allele showed a significantly increased macrophage-mediated neutralisation of fungal conidia (P=0.0003) and, under stimulation conditions, produced higher levels of IFN? mRNA (P=0.049) and IFN? and TNFa cytokines (PLPS-96h=0.057, PPHA-96h=0.036 and PLPS+PHA-96h=0.030 and PPHA -72h=0.045, PLPS+PHA-72h=0.018, PLPS-96h=0.058 and PLPS+PHA -96h=0.0058, respectively). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict the disease (AUC=0.659 vs. AUC=0.564, PLR=5.2•10-4 and P50.000Perm=9.34•10-5). These findings suggest that the IFN?rs2069705 SNP influences the risk of IA and that predictive models built with IFN?, IL8, IL12p70 and VEGFa variants might be used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies., This study was supported by grants PI12/02688 from the Fondo de Investigaciones Sanitarias (Madrid, Spain), PIM2010EPA-00756 from the ERA-NET PathoGenoMics (0315900A), and the Collaborative Research Center/Transregio 124 FungiNet. C.C. is supported by the Fundação para a Ciência e Tecnologia, Portugal (SFRH/BPD/96176/2013). This study also was supported by a donation of Consuelo González Moreno, an acute myeloid leukemia survivor. We thank Astella Pharma Inc. for supporting this work., info:eu-repo/semantics/publishedVersion

The first insight into T. borchii isoprenoid pathway, also known as mevalonic acids pathway (MVA) during ascoma maturation were here discussed . Three genes coding for the most important enzymes of the isoprenoid biosynthesis were characterised, and the activity of the major regulatory enzyme of the MVA was determined in particular during the ascomata maturation. Furthermore several isoprenoids were identified among the volatile compounds produced by ripe T. borchii ascomata

During the different phases of mycorrhizal fungi life cycle, several morphological, genetic and metabolic modifications are induced for both symbiotic partners. These changes are influenced by multiple environmental factors: light, gravity, oxygen, temperature, soil typology, nutrient availability, root exudates (that content sugars) and the presence of particular bacterial populations in the mycorrhizosphere. In the present study we focused on the influence of the host plant and of different nutritional substrates. An in vitro model has been set up, in which plant (Tilia americana) and fungus (Tuber borchii) were close one each other, but physically separated by a membrane, in order to perform a suppressive subtractive library able to find out genes differentially expressed in the pre-symbiotic phase (in the presence of the plant). The results obtained highlighted that in the presence of the plant the fungus shows a major expression of genes involved in hyphal growth, detoxification processes and general metabolism. Furthermore studies has been performed on T. borchii mycelia cultivated in different carbohydrates sources: morphological and molecular investigations highlighted that in the presence of glucose the fungus shows an implemented growth and a major expression of genes involved in hyphal growth, detoxification processes and general metabolism

Truffles are hypogeous ectomycorrhizal fungi belonging to the Ascomycetes, within the species of the genera Tuber which have a great economical importance for the organoleptic properties of their fruit bodies. Morphological descriptions of truffle ascomata development are limited due to their hypogeous habitat: in fact only the mature ascomata produce the typical aroma recognized by trained dogs while the collection of immature truffles is fortuitous. In addition, symbiotic relationships are required for the development of the truffle fruit bodies, which cannot be produced in vitro. Despite some biochemical and molecular studies regarding Tuber borchii fruit body development the molecular mechanisms leading to differentiation and ascospore production remain elusive. We reported the characterization of the T. borchii Tbz1 gene showing a high homology with a zygote-cell-wall protein of the green alga C. reinhardtii (Matters & Goodenough, 1992). Tbz1 is a single copy gene expressed in the early stage of ascomata maturation and absent in the symbiotic tissue. The deduced protein sequence of Tbz1 has transmembrane helices and a signal peptide indicating a membrane localization of this protein. The homologous genes in Tuber puberulum (Tpz1), Tuber aestivum (Taz1) and Tuber brumale (Tbrz1) have been also found. Sequence analysis showed that these genes are identical which strongly suggests that the function of the coded protein has been conserved during the evolution of the truffles. Matters GL, Goodenough UW (1992) A gene/pseudogene tandem duplication encodes a cysteine-rich protein expressed during zygote development in Chlamydomonas reinhardtii.