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SummaryAnimal host defense against infection requires the expression of defense genes at the right place and the right time. Understanding such tight control of host defense requires the elucidation of the transcription factors involved. By using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense. HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection. TFEB was also rapidly activated in murine macrophages upon S. aureus infection and was required for proper transcriptional induction of several proinflammatory cytokines and chemokines. Thus, our data suggest that TFEB is a previously unappreciated, evolutionarily ancient transcription factor in the host response to infection.

(Abstract) The Gram-positive bacterium Staphylococcus aureus is a human pathogen that displays virulence towards the nematode Caenorhabditis elegans. This property can be used to discover genes that are important for virulence in humans, because S. aureus possesses common virulence factors that are used in C. elegans and in humans to cause disease. S. aureus colonizes the C. elegans intestine, establishes an infection, and causes pathogenesis of the intestinal epithelium that ultimately kills the infected animal after 3 to 4 days (Sifri et al., 2003; Irazoqui et al., 2008; Irazoqui et al., 2010). The protocol described here is used to establish the rate of S. aureus-induced C. elegans death, which allows the comparison of wild type and mutant strains and thus ultimately aids in the identification of genes required either for S. aureus virulence or for C. elegans host defense. The assay can also be applied for antimicrobial drug discovery.

Enzyme application in biotechnological and environmental processes has had increasing interest due to its efficiency, selectivity and mainly for being environmentally healthful, but these applications require a great volume of enzymes. In this work the effect of different concentrations of ethanol and 2,5-xylidine on growth and production of laccase by Pycnoporus sanguineus was investigated. In a medium containing 200 mg.L(-1) of 2,5-xylidine or 50 g.L(-1) of ethanol, the maximum activity of laccase was 2019 U.L(-1) and 1035 U.L(-1), respectively. No direct correlation between biomass and activity of laccase was observed for any of the inducers used during the tests. Ethanol concentrations, larger than or equal to 20 g.L(-1), inhibited the radial growth of P. sanguineus. This study showed that ethanol, which has less toxicity and cost than the majority of the studied inducers, presents promising perspectives for laccase production by P. sanguineus.

Simple Summary IgM monoclonal gammopathy of undetermined significance (IgM MGUS) is an early precursor stage of the rare lymphoma Waldenström Macroglobulinemia (WM). Although comparative gene expression studies on WM, IgM MGUS, and normal B-cells (CTRLs) identified several differentially expressed genes, reliable predictors of progression from IgM MGUS to WM have not yet been identified. We performed a microarray study on CD19+ and CD138+ cells of WM vs. IgM MGUS vs. CTRLs to determine gene signatures for both cell populations. We demonstrated that hematopoietic antigens, cell-adhesion molecules, Wnt-signaling, BCR-signaling, calcium signaling, coagulation cascade, and pathways responsible for cell cycle and proliferation were significantly enriched for genes expressed in B-cells of WM vs. IgM MGUS vs. CTRLs. Interestingly, we showed nine genes which displayed the same expression levels in WM and IgM MGUS compared to CTRLs, suggesting their possible role in the risk of transformation of IgM MGUS to WM. Abstract Waldenström Macroglobulinemia (WM) is a B-cell lymphoma characterized by the precursor condition IgM monoclonal gammopathies of undetermined significance (IgM MGUS). We performed a gene expression profiling study to compare the transcriptome signatures of bone marrow (BM) B-cells and plasma cells of 36 WM patients, 13 IgM MGUS cases, and 7 healthy subjects used as controls (CTRLs) by Affymetrix microarray. We determined 2038 differentially expressed genes (DEGs) in CD19+ cells and 29 DEGs genes in CD138+ cells, respectively. The DEGs identified in B-cells were associated with KEGG pathways, mainly involved in hematopoietic cell lineage antigens, cell adhesion/focal adhesion/transmembrane proteins, adherens junctions, Wnt-signaling pathway, BCR-signaling pathway, calcium signaling pathway, complement/coagulation cascade, platelet activation, cytokine-cytokine receptor interactions, and signaling pathways responsible for cell cycle, apoptosis, proliferation and survival. In conclusion, we showed the deregulation of groups of genes belonging to KEGG pathways in the comparison among WM vs. IgM MGUS vs. CTRLs in B-cells. Interestingly, a small set of genes in B-cells displayed a common transcriptome expression profile between WM and IgM MGUS compared to CTRLs, suggesting its possible role in the risk of transformation of IgM MGUS to WM.

The clinical course of WM widely differs among patients, with some manifesting symptoms as a consequence of the monoclonal IgM component or lymphoma infiltration. IgM-MGUS is generally asymptomatic while, in some cases, paraprotein-related manifestations may occur. Patients with IgM-MGUS should perform a regular follow-up as they are at risk of developing WM or other B-cell lymphoproliferative disorders (1.5-2% per year). Although WM typically afflicts the elderly, there are no studies addressing the impact of ECOG performance status and comorbidities on patients' outcome. Furthermore, to our knowledge health-related quality of life (HRQOL) has never been evaluated in this category. The aim of this study is to analyze the impact of diagnosis and patients' characteristics on quality of life. From October 2017, HRQOL was assessed in 103 patients (37 WM with previous or ongoing treatment [tWM]; 29 asymptomatic MW [aWM]; 37 IgM-MGUS) by the administration of EORTC QLQ-C30, HADS, FACT-GOG neurotoxicity and EQ-5D-5L questionnaires. Demographic anamnestic and disease-related data were also collected for each patient. The same questionnaires continue to be administered every 6 months for 3 years, in order to capture changes in HRQOL over time. Patients features are reported in table 1. No significant differences in terms of age, sex distribution, age at diagnosis, months from diagnosis, ECOG performance status, CIRS or number of concomitant medications, were detected among the 3 groups (table 1). As regards CIRS, the organ systems mainly involved resulted: vascular and genitourinary for tWM, genitourinary for aWM and vascular, respiratory and genitourinary for IgM-MGUS. Among the 3 groups no statistical differences were reported when analyzing: EORTC QLQ-C30 global health status, functional scales (physical, role, emotional, cognitive and social functioning) and symptoms scale, EQ-5D VAS score, HADS anxiety and depression scores or FACT-GOG neurotoxicity score. Males had higher global health status and emotional function when compared to females both in IgM-MGUS and WM patients. Higher CIRS score and ECOG status negatively impacted on global health status, physical function, EQ-5D VAS score and anxiety both in WM and IgM-MGUS. WM patients with longer time from diagnosis showed a significantly worse emotional function. Patients-reported symptoms that could be referred to peripheral neuropathy (PN, 39 patients) resulted the only significant parameter negatively impacting on HRQOL (global health status, functional and symptoms scales according to EORTC QLQ-C30 and EQ-5D VAS score) and also affecting HADS anxiety score. The diagnosis of PN was confirmed by neurologic tests only in 16/39 subjects that, compared with the rest of the population, showed older age (p .019), older age at diagnosis (p . 015) and higher ECOG status (p .005). In these patients, EORTC QLQ-C30 detected a reduced cognitive function (p .0031), while HADS a greater perception of anxiety (p .0015). No differences were recorded for EQ-5D VAS score or HADS depression scale. In conclusion, in our series diagnosis per se didn't seem to affect HRQOL which was negatively influenced by high ECOG status and comorbidities. Emotional function meaningfully deteriorated as the time lapse from diagnosis became longer. Quality of life was significantly altered in patients reporting symptoms of PN and this was confirmed by all the questionnaires. Longer follow up is needed to confirm these preliminary data. Disclosures Montillo: Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau. Tedeschi:Janssen: Consultancy, Speakers Bureau; AbbVie: Consultancy; Gilead: Consultancy.

Bing Neel Syndrome (BNS) is defined as direct central nervous system involvement of Waldenstrom’s macroglobulinemia. BNS is usually a late event, although an incidence of 30% to 36% has been described in large series of previously untreated patients. A wide variety of clinical manifestations and radiologic findings for BNS have been reported in published data, depending on the site and type of infiltration. In addition to the radiologic findings, the diagnostic approach includes lymphoplasmacytic cell quantitation and flow cytometric analysis of the cerebrospinal fluid (CSF). Recently, the evaluation of MYD88 L265P mutation in the CSF has been proposed as a possible diagnostic biomarker for BNS. We describe the case of a 58-year-old patient with BNS. The detection of MYD88 L265P mutation in the CSF contributed to the diagnosis and to the sequential monitoring of minimal residual disease. In the future, the use of CSF sequential molecular monitoring could play an important role in treatment decisions.