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Magnetic hybrid nanomaterials for the photodegradation of microcontaminats in aqueous environment

Background Targeted therapy with Tyrosine-Kinase-Inhibitors (TKIs) totally modified the course of treatment of Chronic Myeloid Leukemia (CML). The objectives and the needs of treatment have been modified during the last years and the discontinuation of therapy is now a feasible aim. However, a lot of biological data acquired in the last twenty years, showed that degree and mechanisms of Leukemic Stem Cells (LSCs) clearance during TKI treatment are not clearly established as well as the predictive criteria for a stable and prolonged Treatment Free Remission (TFR). The multicentre, prospective, single-arm PhilosoPhi34 study (EudraCT: 2012-005062-34) was designed by the Rete Ematologica Lombarda (REL), to verify the in-vivo activity and time-course of first-line Nilotinib (NIL) therapy on Bone Marrow (BM) CD34+/lin-Ph+ cells clearance. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin- cells at diagnosis and at 12 months (mos) of treatment, for the first 30 evaluable pts, was included. Preliminary GEP data suggested a correlation between different NFKBIA expression at diagnosis and at 12 mos and the achievement of a deeper Molecular Response (MR) (Pungolino et al, AJH 2018). We report here some results of GEP analysis on all enrolled evaluable pts and their possible correlation with clinical data. Methods BM cells were collected and stored at diagnosis and at 12 mos of treatment. CD34+/lin- cells were purified with a Diamond CD34 Isolation Kit Miltenyi (97% of purity). For GEP analysis we used Affymetrix HG-U133 Plus 2.0 microarray and Genechip platform (Affymetrix) and the Affymetrix GeneChip Scanner 3000. Data was pre-processed and normalized using the Robust Multi-array Average (RMA) algorithm. The Significant Analysis of Microarrays (SAM) was used to identify genes with statistically significant changes in expression. P-values were corrected for multiple testing using false discovery rate, for differentially expressed genes confirmation. We chose to analyse different expression of NFKBIA (the inhibitor of NF-kB onco-gene) in order to confirm the preliminary data reported on the first 30 analysed pts. Pts were monitored according to ELN-recommendation. Biological data were correlated with MR at 3, 12 and 36 mos of therapy. We use Fishers test to compare unbalanced group. Results Out of the 87 enrolled pts, 80 completed the first 12 mos of treatment and 78 (1 failure and 77 CCyR) were evaluable for GEP analysis. We observed 2726 genes symbol differentially expressed of which 1868 are coding genes. Among these, JAK-2 showed a down regulation at 12 mos (p: .024). JAK-2 expression ranged from 2.62 to 4.95 at diagnosis and from 1.48 to 5.58 at 12 mos. Only 26/78 pts increased JAK-2 expression that was > 4 in 1/26 pts, at diagnosis; 2/26 (7.69%) pts showed a H Sokal. Other 52/78 pts decreased JAK-2 expression that was ≥ 4 in 21/52 pts, at diagnosis; 10/52 (19.23%) pts and 6/21 (28,57%) pts showed a H Sokal. Similarly, when we compared low JAK-2 expression (< 3.5) vs vary high expression (≥ 4) 2/21 vs 6/22 pts had H Sokal (9.52% vs 27.27%; p: .0057). Considering the role of JAK-2 and NFKBIA in cell regulation and survival, we evaluated how the combination of their different expression impact on MR (i.e. NFKBIA increased expression/JAK-2 decreased expression vs NFKBIA decreased expression/JAK-2 increased expression). Data are reported in Table 1 and 2. Conclusion GEP analysis showed a down regulation of JAK-2 expression after 12 mos of first line NIL treatment, in 78 early chronic phase CML pts. Data suggest that high expression of JAK-2, at diagnosis, correlate with H Sokal score. However, H Sokal pts with a JAK-2 down regulation, obtain during treatment similar MR compared to L Sokal pts. Additionally, the study confirms our preliminary observation on 30 pts , concerning the role of NKBIA up - regulation in increasing percentage of earlier and deeper MR . The better condition of NFKBIA and JAK-2 expression (up regulation of NFKBIA and down regulation of JAK-2) is associated with a higher percentage of early MR3 and optimal responses over time, despite the higher number of H Sokal pts in this group. A study with NIL as first line treatment combined with low dose of JAK-2 inhibitor and a natural inhibitor of NF-kB (such as curcuma), during the first year of treatment, to increase the deeper MR rate and the probability of TFR is warrented. Disclosures Rossi: Sandoz: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Teva: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Novartis: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Treated urban wastewater is currently widely reused to compensate for dwindling water supplies, as it is considered to be a reliable alternative water source. In addition, the increasing demand for food due to the expanding world population, both in respect to food security and food safety, and therefore for irrigation water, renders wastewater reuse a practice of utmost importance. As a consequence, sustainable and safe urban water cycles are presently of high priority on the policy agendas of many countries around the world. Although reuse has a number of benefits and major advances have been made with respect to producing treated effluents for reuse (e.g., successful removal of metals, reduction of chemical oxygen demand and of other pollution parameters), several important questions are still unanswered and barriers exist regarding the safety/sustainability of reuse practice. Knowledge gaps associated with wastewater reuse include the following: (a) possible elemental interactions that may influence the accumulation of metals/elements in the soil and their subsequent uptake by plants and crops, (b) the fateof organic microcontaminants in receiving environments, and (c) the epidemiological potential of antibiotic resistant bacteria and/or resistance genes (ARB&ARG) released in the environment via treated effluent. Possible implications on food-chain contamination (biomagnification) require much attention, since treated wastewater is not exempt of such contaminants. The effluents’ residual organic matter after conventional treatment consists of a number of recalcitrant organic compounds including potential endocrine disrupting compounds, many types of pharmaceuticals including antibiotics, disinfection by-products, personal care products, metabolites and transformation products, other organic substances (i.e. pesticides, surfactants, biocides, etc.), and not to be forgotten ARB&ARG. In fact, preliminary results suggest that the relative abundance of certain ARG or ARB may even be enriched during the wastewater treatment (Rizzo et al. 2013). This leads to their subsequent release in the terrestrial and aquatic environments through disposal and reuse applications, and the level of risk to environmental and human health is yet to be evaluated. Contamination of the environment, food chain, drinking water, etc with ARB&ARG is presently considered to be a serious public health problem. For this reason, the World Health Organization (WHO) (WHO 2013) characterized the development of AR as one of the major global threats to society and recommends intensive monitoring for the identification/surveillance of critical hot spots (e.g., wastewater treatment plants), aiming at reducing its propagation. In September 2014, a national strategy (The White House 2014) was announced in the USA by the White House that lays out a series of steps to address the decreasing effectiveness of antibiotics, many being similar to those identified by WHO. According to the European Centre for Disease Prevention and Control, it is estimated that infections caused by a subset of ARB are responsible for about 25,000 deaths in Europe annually. In addition, the extra healthcare costs and productivity losses due to ARB are estimated to reach EUR 1.5 billion (European Centre for Disease Prevention and Control 2013). In the USA, equally dramatic numbers are reported by the Centers for Disease Control and Prevention, with AR infections killing at least 23,000 people and sickening 2 million each year (The White House 2014). All these issues have not received significant attention in the framework of the wastewater reuse practice. The EU- COST Action ES1403 (NEREUS) aims at consolidating the existing scattered data related to wastewater reuse and will address the open challenges associated with it. It will provide the platform for a systematic consolidation of data and standardization of methods for assessing emerging hazards associated with wastewater reuse. The Action is chaired by D. Fatta-Kassinos from Nireas-International Water Research Center and Department of Civil and Environmental Engineering of the University of Cyprus and vice-chaired by C. Manaiafrom Escola Superior de Biotecnologia, Universidade Católica Portugeusa.