Journal articles on the topic 'Concentration porteur charge'

Management literature related to globalisation and the need for organisations to gain a competitive advantage has grown in prominence over the past two decades (Caves 1982; Porter 1985, 1990, 1991, 1998; Barney 1995; Peteraf 1993; Barner 1996; Duncan, Ginter & Swayne 1998; Thomas, Pollock & Gorman 1998; Zahra 1998; Zahra & O'Neil, 1998; Gupta & Govindarajan 2001). Concomitant with globalisation and competitive advantage are issues related to achieving successful organisational change, since it logically holds that any activity to increase an organisation's effectiveness necessarily involves some sort of change. Much of the research attention in the past has focussed on strategies for implementing change, including overcoming resistance, rather than developing theories which lead to a greater understanding of the processes of change. Early research (Coch & French 1948; Ginzberg & Reilly 1957; Lewin 1951) reflect the historical concentration on how best to implement change; this tradition is more recently exemplified by Carnall (1999) who examines practical techniques for achieving change in organisations. However, literature relating to the theory of change remains fragmented and inconclusive.

Management literature related to globalisation and the need for organisations to gain a competitive advantage has grown in prominence over the past two decades (Caves 1982; Porter 1985, 1990, 1991, 1998; Barney 1995; Peteraf 1993; Barner 1996; Duncan, Ginter & Swayne 1998; Thomas, Pollock & Gorman 1998; Zahra 1998; Zahra & O'Neil, 1998; Gupta & Govindarajan 2001). Concomitant with globalisation and competitive advantage are issues related to achieving successful organisational change, since it logically holds that any activity to increase an organisation's effectiveness necessarily involves some sort of change. Much of the research attention in the past has focussed on strategies for implementing change, including overcoming resistance, rather than developing theories which lead to a greater understanding of the processes of change. Early research (Coch & French 1948; Ginzberg & Reilly 1957; Lewin 1951) reflect the historical concentration on how best to implement change; this tradition is more recently exemplified by Carnall (1999) who examines practical techniques for achieving change in organisations. However, literature relating to the theory of change remains fragmented and inconclusive.

The effects of changes in H+ activity on the adsorption and intracellular accumulation of Zn by Chlamydomonas variabilis Dangeard have been studied over the pH range 7–5. Other experimental variables included the dissolved free Zn concentration, [Zn2+]b, the antecedent growth conditions (pH of the growth medium = 7, 6, or 5), and the physiological state of the harvested cells. After short-term incubations with 65Zn, algal cells were collected and the concentrations of EDTA-extractable Zn ([Zn]a ~ surface-bound Zn) and nonextractable Zn ([Zn]c ~ transported Zn) were determined. Values for [Zn]a and the flux (F) of Zn across the cell membrane decreased with increasing culture age, but cells harvested at comparable growth stages behaved similarly in the subsequent short-term incubations with Zn, irrespective of their original growth pH. In the incubation solutions, however, pH changes did affect both [Zn]a and F. At constant [Zn2+]b, a decrease in pH from 7 to 5 led to lower values of [Zn]a (~70%), suggesting either a pH-induced change in algal surface potential or a competition between H+ and Zn2+ for specific binding sites at the cell surface; a concomitant decrease in Zn flux (50–65%) was noted. The decrease in pH from 7 to 5 also had the effect of minimizing the dependence of Zn flux on the Zn2+ concentration. Two Zn transport mechanisms may coexist in C. variabilis cells, one involving a diffusion pathway sensitive to pH changes in the range 7–5 and the other a high-affinity porter system operative at both pH 7 and pH 5. These results suggest that the net effect of lake acidification may well be a decrease in the overall bioavailability of Zn to algae.

Amino acid/K+ symport (cotransport) across a model epithelium, the lepidopteran midgut, is energized by an electrogenic H+ V-ATPase (H+ pump) in parallel with an electrophoretic K+/H+ antiporter (exchanger). Attempts to analyze this process using well-known equilibrium thermodynamic equations (Nernst, Gibbs), diffusion equations (Nernst, Planck, Einstein, Goldman, Hodgkin, Katz) and equations based on Ohm's law (Hodgkin, Huxley) have all encountered major difficulties. Although they are useful for analyzing nerve/muscle action potentials, these state equations assume that brief perturbations in membrane conductance, gm, and membrane voltage, Vm, occur so rapidly that no other parameters are significantly disturbed. However, transport studies often extend for minutes, even for hours. Perturbation of one parameter in complex transport systems invariably results in a state change as all of the other elements adjust to the prolonged stress. The development of a comprehensive mathematical treatment for transport systems that contain pumps and porters (transporters) has been hampered by the empirical nature of the concept of membrane permeability and conductance. The empirical definition of permeability was developed before pumps and porters were known. Thus, 'permeability' is a gross parameter that, in practice if not in theory, could describe all transport pathways including pumps, porters and channels. To surmount these difficulties, we have applied ionic circuit analysis to vesicular systems containing insect midgut transport proteins. In this analysis, pumps, porters and channels, as well as ionic concentration gradients and membrane capacitance, are components of ionic circuits that function to transform metabolic energy (e.g. from ATP hydrolysis) into useful metabolic work (e.g. amino acid uptake). Computer-generated by an H+ V-ATPase to K+/2H+ antiport and amino acid/K+ symport in the lepidopteran midgut.

AbstractWhile a large body of the literature on environmental policies has focused on the productivity impacts of regulations, less attention has been given to the link between environmental policies and market competition. In this paper, I develop a tractable model that incorporates variable mark-ups to study how a competitive environment is affected by environmental policies in a market with firm heterogeneity and endogenous abatement technology choice. The findings of this study are consistent with the Porter Hypothesis in the sense that environmental regulations motivate abatement technology adoption and enhance productivity and environmental quality. However, the productivity gain is mainly driven by reallocation of resources across firms rather than the induced abatement technological change. Tougher regulations harm the competitive environment by increasing average prices and market concentration. Social welfare also drops because in the absence of strong competition fewer variates are produced in equilibrium.

The concept of electrical circuit analysis is extended to include components found in membrane ionic transport systems. As in classical electrical equivalent circuits, resistors and capacitors are used to represent ion channels and the membrane capacitances, respectively; batteries represent energy sources driven by chemical reactions. In the extensions proposed, energy stored in various ionic concentrations is treated as charges on compartmental capacitors; symporters and antiporters are treated as energy-coupling devices analogous to transformers in alternating current electrical circuits. Pumps are shown to be special cases of porters in which the input circuit derives its energy from a chemical reaction. Using these components, circuit diagrams are drawn for several examples of membrane ion transport systems. By applying appropriate circuit analysis techniques, these diagrams facilitate the quantitative description of the energy distributions throughout the system.

Abstract Background: Beta thalassemia major patients (pts) are at an increased risk of heart failure, due to the deposition of iron in the heart causing myocardial siderosis. Intensive long-term iron chelation therapy (ICT) is required to obtain a normal myocardial T2* (mT2* >20 ms). Previously published studies suggested that cardiac iron removal lags changes in liver iron, and liver iron concentration (LIC) may affect the rate of removal of cardiac iron (Porter et al, ASH 2013). The objective of these analyses was to evaluate the association of the severity of LIC levels with the change in mT2* responses in pts with myocardial siderosis when treated with deferasirox (DFX) and deferoxamine (DFO) for up to 24 months (mo) in the CORDELIA study. Due to the very low pt numbers in the DFO arm, the results for these pts are not presented here. Methods: The study design, inclusion, and exclusion criteria have been reported previously (Pennell et al, Am J Hematol. 2015). Pts were categorized into LIC <7, 7 to <15 and ≥15 mg Fe/g dry weight (here after mg/g) both at baseline (BL) and specific visits, to assess the relation of absolute LIC and changes in LIC overtime, with mT2* and cardiac iron concentration (CIC), respectively. During the study, mT2* (ms), and LIC (mg/g) were measured every 6 mo at the same time point. CIC (mg/g) was analyzed as a post hoc parameter derived from mT2*. The change in mT2* was assessed as geometric mean (Gmean)±coefficient of variation (CV), ratio of the Gmean at specific time points divided by that at BL (Gmean at specific time point/Gmean BL) and both CIC and LIC as mean±SD, unless otherwise specified. Results: Of 197 pts, 160 (81.2%) completed 12 mo of treatment and 146 (74.1%) entered into the extension study whereas 103 pts continued on initially assigned treatment. Pts completing 24 mo of treatment included 65 (87.8%) of 74 pts (mean age 20.1±6.9 years, 59.5% male) on DFX and the results for these pts are presented as follows. Average actual doses (mg/kg/d) were 26.7±8.9, 31.5±7.4, 38.0±2.9 for LIC <7, 7 to <15, ≥15, respectively, during the extension study. The LIC levels for pts categorized by LIC <7, 7 to <15 and ≥15 improved from BL to Mo 24 as follows: 72% decrease (mean absolute change, -15.1±14.1), 66% decrease (-26.6±13.0), and 19% decrease (-10.2±15.7), respectively. For pts with BL LIC <7, 7 to <15, ≥15, mT2* improved from BL to Mo 24 as follows: 43% increase (14.0±18.1 to 21.6±31.1; mean abs change, 7.8±4.0), 50% increase (12.3±34.4 to 19.1±46.4; 8.0±6.0), and 30% increase (11.1±30.8 to 14.5±40.8; 4.1±5.0). The CIC values improved from BL to Mo 24 by 38% (1.8±0.4 to 1.1±0.5), 40% (2.3±0.9 to 1.4±0.7), and 23% (2.6±1.0 to 1.9±1.0), respectively. The mT2* responses for pts categorized according to visit specific LIC levels (LIC <7, 7 to <15, ≥15) from BL to Mo 12 were 22% increase (mean abs change, 3.7±4.3) in LIC <7, 21% increase (2.7±2.0) in LIC 7 to <15, and 7% increase (1.5±3.2) in LIC ≥15. From BL to Mo 24, mT2* increased by 51% (mean abs change, 7.8±5.3), 35% (4.1±2.5), and 11% (2.0±4.4), respectively. The CIC levels improved from BL to Mo 24 by 40% (mean abs change, -1.0±0.8) in LIC <7, 31% (-1.0±0.6) in LIC 7 to <15, and 6% (-0.1±0.8) in LIC ≥15. The change in mT2* (Gmean ratio) at Mo 6, 12, 18 and 24 are shown in the Figure A. The mT2* response was higher in pts who achieved a lower LIC category (LIC <7) at respective time points and this change in mT2* was more apparent at 18 and 24 mo of treatment with DFX. Discussion: Overall, DFX treatment resulted in a substantial decrease in LIC and improved mT2*. These results suggest a greater difference in mT2* improvement and CIC reduction in pts who achieved lower LIC during treatment with DFX. This divergence was progressive with time, being maximal at Mo 24. Thus, a therapeutic response in LIC with DFX may be associated with a greater likelihood of improving mT2*. Pts with high LIC ≥15 may require an effective long-term treatment with higher doses of ICT to have an improvement in mT2*, suggesting that cardiac iron removal is likely to be slow in heavily iron overloaded pts. These results are consistent with the previous report which showed a significant decrease in LIC and increased mT2* responses at Mo 36 in pts who attained lower end-of-year LIC levels when treated with DFX (Porter et al, ASH 2013) and highlight the potential value of monitoring the liver and cardiac responses during ICT. To further understand the kinetics between liver and cardiac iron removal, prospective investigation is warranted. Disclosures Pennell: Novartis: Consultancy, Research Funding; Apotex: Consultancy, Research Funding. Porter:Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. Piga:Acceleron: Research Funding; Cerus: Research Funding; Apopharma: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene Corporation: Honoraria. Han:Novartis: Employment. Vorog:Novartis: Employment. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract Background Serum ferritin is regularly used to assess response to chelation therapy and correlates significantly with liver iron concentration (LIC) particularly when LIC is <7 mg Fe/g dry weight (dw) and serum ferritin is <4000 ng/mL. The absence of a serum ferritin decrease in the first months of a new chelation regime may be interpreted as a lack of response with respect to decreasing body iron load. However, sequential LIC determination (where available) has indicated that many of these patients do indeed have a decrease in LIC. This clinical experience requires greater understanding, particularly the nature of the LIC and serum ferritin relationship at baseline serum ferritin values ≥4000 ng/mL. The aim of this post-hoc analysis of the EPIC study was to gain insight into the relationship between serum ferritin and LIC in response to deferasirox over 1 year, in a large patient cohort, so that serum ferritin trends can be more clearly interpreted and evidence-based practical guidance be given for patients with transfusion-dependent thalassemia (TDT). Methods TDT patients were recruited from 25 sites, received 1-year of deferasirox treatment and had serum ferritin and R2 magnetic resonance imaging (R2-MRI)-assessed LIC measurements at baseline and 1 year. Summary statistics are provided for serum ferritin and LIC responders (decrease, any change from baseline <0) and nonresponders (increase or no change, any change from baseline ≥0), and for baseline serum ferritin categories (≥4000 vs <4000 ng/mL). Results Of the 374 patients analyzed in the EPIC liver MRI substudy, 317 had TDT, of which 72.7% (n=226) had a serum ferritin response and 27.3% (n=85) had no response. Importantly, after 1 year LIC decreased in approximately half of serum ferritin nonresponders (51.8%; n=44; Table) and in 79.6% of serum ferritin responders (n=180). Median (min, Q1, Q3, max) change in LIC (mg Fe/g dw) was –5.4 (–38.5, –11.7, –0.9, 15.4) in serum ferritin responders and –0.2 (–18.4, –2.6, 2.7, 19.6) in nonresponders. Median (range) transfusional iron intake (mg/kg/day) was similar in serum ferritin responders (0.30 [0.01–1.49]) and nonresponders (0.37 [0.02–1.00]). Median deferasirox dose (mg/kg/day) was higher in serum ferritin responders than nonresponders (28.1 [9.8–40.4] vs 23.7 [9.7–37.9]). Evaluation of responses by baseline serum ferritin showed that a greater proportion of serum ferritin responders with baseline serum ferritin <4000 ng/mL also had decreased LIC (88.7% [n=102]; Table), compared with serum ferritin responders with baseline serum ferritin ≥4000 ng/mL (70.3% [n=78]). However, serum ferritin baseline category had no effect on the proportion of patients who decreased LIC despite having no serum ferritin response (52.6% [n=30], <4000 ng/mL; 50.0% [n=14], ≥4000 ng/mL; Table). There was little change in median LIC in serum ferritin nonresponders after 1 year regardless of baseline serum ferritin value (–0.3 [–13.5–18.7] for <4000 ng/mL and 0.2 [–18.4–19.6] for ≥4000 ng/mL). Assessment by change in serum ferritin and LIC quadrants indicated that patients without serum ferritin or LIC response had the lowest baseline median (range) serum ferritin and LIC (2155 [480–9725] ng/mL; 11.9 [1.8–37.5] mg Fe/g dw; n=41), and received a lower median deferasirox dose (23.7 [9.7–36.0] mg/kg/day). Overall, median LIC decrease (mg Fe/g dw) was smaller in patients with baseline serum ferritin <4000 ng/mL (n=172) than in those with serum ferritin ≥4000 ng/mL (–2.8 [–38.5–18.7] vs –4.9 [–31.1–19.6]; n=139). Median iron intake was similar between groups. Discussion and conclusions A decrease in LIC was seen in ~80% of serum ferritin responders after 1 year of deferasirox; a greater proportion of serum ferritin responders (88%) decreased LIC when baseline serum ferritin was <4000 ng/mL. Importantly, among patients with no serum ferritin response up to half may be responding with respect to iron balance, indicating that a lack of serum ferritin response should be interpreted with caution. However, since a decrease in serum ferritin predicts a decrease in LIC in 80% of patients, MRI measurement (where available) should be prioritized for patients with serum ferritin increase/no change. Overall, serum ferritin response can help predict LIC response, but in some patients treated with deferasirox, serum ferritin may not accurately reflect removal of iron from the body. Figure 1 Figure 1. Disclosures Porter: Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy; Cerus: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Taher:Novartis: Honoraria, Research Funding. Sutcharitchan:Novartis: Research Funding. Aydinok:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Chakravarty:Novartis: Employment. El-Ali:Novartis: Employment.

Abstract Abstract 5019 Background: MDS patients receiving chronic transfusions can develop significant iron accumulation in key organs such as the liver following 10–20 transfusions (Porter et al. BJH 2001). The diagnosis and monitoring of iron overload, as well as the effect of iron chelation therapy in MDS patients, is often based on serum ferritin (SF), with limited data on liver iron concentration (LIC), primarily due to the biopsy-related increased risk of bleeding and infections in these patients. However, LIC is clinically a more robust and direct measure of body iron burden and with the availability of non-invasive determination of LIC by MRI, LIC assessment has become more practical in MDS patients. This pooled analysis focuses on LIC assessments from a population of 71 MDS patients who completed 1 year of treatment with deferasirox (Exjade®), including assessment of the relationship between LIC vs SF and alanine aminotransferase (ALT). Methods: Analysis is based on 1-year pooled data from iron-overloaded patients with MDS who were enrolled in 4 open-label single-arm deferasirox studies: US02 (Low/Int-1 MDS patients, starting dose 20 mg/kg/day); 2409 (MDS patients with life expectancy >1 yr, starting dose 10–30 mg/kg/day); 108 (MDS patients with life expectancy >1 yr, dosing 5–40 mg/kg/day), and 2204 (Low/Int-1 MDS patients, starting dose 10–30 mg/kg/day). LIC was assessed in the US02, 2409 and 2204 studies using R2 MRI (St Pierre et al. Blood 2004). In the 108 study, LIC was assessed by magnetic liver susceptometry using a superconducting quantum interference device (SQUID) or ultrasound-guided percutaneous liver biopsy; LIC values obtained by SQUID were multiplied by a factor of 2 to correct for the underestimation of LIC by SQUID compared to biopsy (Porter et al. EJH 2008). Datasets were pooled for baseline (BL) characteristics, as well as LIC, SF and ALT at BL and end of study (EOS). Correlations were evaluated on a Pearson's correlation coefficient. Results: 71 patients (56.3% male) were assessed with a mean age of 65 years (range 16.5–82.0). Mean transfusional iron intake ± SD was 0.31 ± 0.12 mg/kg/day. Mean actual deferasirox dose was 19.6 ± 6.5 mg/kg/day. At BL, mean ± SD LIC was 20.5 ± 14.6 mg Fe/g dw (BL LIC <7 mg Fe/g dw, 21.1%; ≥7 mg–≤15 mg Fe/g dw, 23.9%; and >15 mg Fe/g dw, 54.9%). Median BL SF was 2620 ng/mL (range 538–12,639) (BL SF ≤2500 ng/mL, 47.9%; >2500–≤5000 ng/mL, 32.4%; and >5000 ng/mL, 15.5%). With 1 year of DFX, mean ± SD LIC decreased to 13.9 ± 13.1 mg Fe/g dw (mean absolute change –6.6 mg Fe/g dw). In patients with BL LIC <7 mg Fe/g dw (n=15), LIC was maintained with a mean absolute change of 1.0 ± 2.8 mg Fe/g dw, whereas in patients with BL LIC ≥7 mg Fe/g dw (n=56), LIC was reduced by –8.6 ± 10.7 mg Fe/g dw from BL. The proportion of MDS patients with LIC ≥7 mg Fe/g dw reduced from 78.9% at BL to 59.2% at EOS, with 50.7% of patients achieving a decrease in LIC of ≥30%. Median SF decreased to 2035 ng/mL (range 158–10520 ng/mL) with median absolute change from baseline of –630 ng/mL. There was a significant correlation between BL LIC and SF (R=0.548; P<0.0001). Change in LIC significantly correlated with change in serum ferritin (R=0.336; P=0.0042, Figure A). Mean ALT decreased from 55.9 to 38.9 U/L (absolute change –17.0). The change in LIC correlated with the change in ALT (R=0.397, P=0.0006, Figure B). Conclusions: This pooled analysis in a large cohort of transfusion-dependent MDS patients with LIC assessment shows significantly elevated LIC, with a high proportion of patients (55%) having severely elevated LIC of >15 mg Fe/g dw, a level known to markedly increase liver dysfunction and other iron overload-related complications. One year of treatment with deferasirox produced relevant reductions in LIC, an outcome possibly indicative of a clinical benefit. SF and ALT (an important indicator of liver function) also decreased, with reductions correlating with those of LIC. These findings indicate that correction of moderate-to-severe iron overload in MDS patients is associated with a parallel improvement in liver function. Disclosures: Gattermann: Novartis Pharma: Honoraria, Research Funding. Greenberg:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Habr:Novartis Pharma: Employment. Kpamegan:Novartis Pharma: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

The article deals with the role of clusters in today’s global economy. It is noted that in today’s economic environment it is difficult to overestimate the role of clusters in competition, which has changed significantly and continues to change due to the increased amount of information and knowledge about risk in the global economy. Considering the role of clusters in today’s global economy, it is noted that in modern scientific literature there is no single and generally accepted definition of a cluster as such. Different scholars and economists understand and interpret this concept variously. M. Porter gives the most accurate definition of the cluster. The main characteristics of clusters are considered, namely: geographical concentration, specialization, multiplicity of economic agents. The goals for which clusters are usually directed are given, namely: increase of competitiveness of cluster participants due to introduction of new technologies; reducing costs and improving the efficiency of relevant high-tech services through the synergy effect and unification of approaches in logistics, engineering, information technology, quality management, etc.; providing employment in the context of largescale enterprise reforming and outsourcing; consolidated lobbying of the cluster members’ interests in different authorities. The advantages of the cluster model for the development of the Ukrainian industry are considered and it is stated that among all the advantages of the cluster approach, the most important is the access to innovations, knowledge. It is stated that clusters can be formed in both traditional industries and high-tech areas, and very often different educational establishments or research structures serve as a specific center for cluster formation. It is concluded that within the state, clusters play the role of points of growth of the internal market and ensure the promotion of goods and services produced by them to international markets. This, in turn, contributes to the enhancement of the country’s international competitiveness on the whole, due to a number of advantages inherent in the cluster form of interaction between large, medium and small enterprises in all areas of business relations. One of the directions of socio-economic development of Ukraine, to increase its competitiveness, should be the support and development of territorial production clusters.

Studies have consistently shown that conditions experienced during the periconceptional period including culture in vitro and maternal diet composition can profoundly alter the development of the embryo/fetus and can result in adult diseases such as obesity, hypertension, and cardiovascular disease. This programming occurs during the pre-implantation period. Here, we have examined blastocyst phenotype changes in response to maternal protein undernutrition during the pre-implantation period and determined whether such adaptations are stable through a change in environment. Embryos were flushed at Day 3.25 to 3.75 from naturally mated MF1 mice fed either a control (NPD) or low-protein diet (LPD) from day of plug. Blastocysts were differentially labeled using the TNBS-anti-DNP-complement method with propidium iodide and Hoechst, and cells were counted on z-series with overlays using Metamorph software (Molecular Devices, Sunnyvale, CA). For outgrowths, blastocysts flushed from LPD or NPD mothers were placed into KSOM supplemented with 10% FCS and amino acids at uterine fluid concentrations (Porter et al. 2003 Pediatr. Res. 53, 46A abst). Outgrowths were cultured for an additional 96 h and scored daily with final 4′,6-diamidino-2-phenylindole (DAPI) nuclei counts. Neither total cell numbers nor lineage divergence was affected by maternal diet until just before implantation (Day 3.75) when blastocysts from LPD mothers had significantly more total cells due to an increase in trophectoderm (TE) compared with NPD blastocysts (ANOVA; Table 1). Upon outgrowth, LPD embryos spread over a greater area although with similar nuclei numbers compared with NPD blastocysts. Moreover, inhibition of the mTOR signaling pathway with rapamycin (rapa) showed the expected dose-responsive decrease of spreading in NPD but not in LPD outgrowths (Table 1). Our data suggest a compensatory upregulation of the TE lineage after mild maternal protein undernutrition. This response becomes evident just before implantation and is, together with altered nutrient sensing and signaling sensitivity, sustained throughout peri-implantation development in vitro regardless of culture environment. Thus, we show that adaptations evident by the blastocyst stage and induced by maternal environment can subsequently be memorized and are likely to contribute to long-term programming of phenotype independent of that environment. Table 1.Blastocyst and peri-implantation development respond to maternal diet Funding by DOHaD, Gerald Kerkut Trust, and NICHD are gratefully acknowledged.

Abstract ICL670 (deferasirox) is an orally active iron chelator, intended as once daily mono-therapy for the treatment of transfusional iron overload, which has undergone extensive multi-centre Phase II and Phase III trials. Data from such studies suggest that 20mg/kg as a single daily dose will achieve iron balance in the majority of transfusionally dependent patients, whereas 30mg/kg/day typically achieves negative iron balance (Cappellini, Abstract 3619, ASH 2004) (Porter, Abstract 3193, ASH 2004). Patients with transfusion dependent anaemia and iron overload who were entered into these multi-centre studies at UCL Hospitals had myocardial T2* CMR performed at the Royal Brompton Hospital, as part of their routine monitoring, in line with previous clinical management at our centre. Study 108, a non-randomized study, included poorly chelated patients with -thalassemia and other iron overload conditions receiving regular blood transfusion: all patients received 10-30mg/kg/day of ICL670. Study 107 consisted exclusively of transfusion dependent -thalassemia patients, randomized to receive either 8–10h sc DFO (30–50mg/kg/day) or ICL670 (10–30mg/kg/day) with doses stratified for baseline liver iron concentration (LIC). We report here changes in cardiac T2*, LIC and serum ferritin, as well as LVEF in all patients on these two studies treated at UCLH for a mean of 13.1± 0.78 months, in whom CMR was obtained. In a total of 23 patients treated with ICL670, mean age 24.6y (range 9–50y), 18 with transfusion dependent -thalassaemia and 6 other iron overload conditions (2 Pyruvate kinase deficiency, 2 sideroblastic anemia, 2 Diamond Blackfan Anemia), myocardial T2* improved significantly from a pre-treatment geometric mean of 18.0ms to 23.1ms (p = 0.013, paired student t test). In the same patients, serum ferritin fell significantly from 3173 ±410 μg/L to 2451 ±242μg/L (p= 0.023, paired student t test) and LIC fell significantly from 18.3 ±2.2 mg/g dry wt to 10.0 ±1.49 (p= 0.0002, paired student t test). There was no significant change in LVEF before or after treatment over the same period. Patients treated in the DFO arm of study 107 (n=8) also showed a small non-significant increase in myocardial T2* from 18.1 ms to 21.1 ms (p= 0.11), These studies suggest that once daily mono-therapy with ICL670 will be effective at improving myocardial T2* and by inference myocardial iron loading in a wide range of patients with transfusional iron overload. Prospective randomised controlled studies in larger patient numbers are now indicated.

Abstract Chelation treatment of patients with iron overload from chronic blood (RBC) transfusion needs continuous monitoring of iron stores, iron influx rates from RBC, chelation dose rates, and compliance. Molar chelator efficacy depicts the combined effect from these variables. Treatment should always aim to maximize the efficacy of a certain chelator in an individual patient in order to reduce organ damage from iron toxicity. In a prospective trial on the oral chelator deferasirox, a total of 12 patients with b-thalassemia major have been followed by SQUID biomagnetic liver susceptometry in intervals of 6 to 12 months over a time period of up to 38 months under deferasirox. Patients were initially on deferoxamine (DFO, Desferal®) and then participated in an international multi-center trial randomized for s.c. DFO and the oral chelator deferasirox (DSX, Exjade®). Liver iron concentration LIC (μg/g-liver wet weight), liver volumes, RBC transfusion rates, chelation dose rates, and compliance from tablet counts were assessed. Total body iron stores were calculated from total liver iron taking into account that 70 – 90 % of the total body storage iron is accumulated in the liver. For each chelation interval, molar efficacies were calculated from the daily iron input rate due to RBC plus the change in total body iron per interval time (= mobilized iron rate), and the molar dose rate of DFO or DSX (Fischer et al: Ann N Y Acad Sci2005; 1054: 350–7), equation 1. \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[Molar\ efficacy\ [\%]\ =\ mobilized\ iron\ rate/molar\ chelator\ dose\ rate\] \end{document} LIC values were in the range of 836 to 8404 with a median value of 2424 μg/g-liver, while ferritin levels were between 911 and 13609 μg/l with a median ratio of ferritin-to-LIC of 1.0 ((μg/l)/(μg/g)) (range: 0.4 to 3.2). The median molar dose rates for DFO and DSX were 3.2 and 1.6 mmol/d, respectively. For each patient, the molar efficacies for DFO and DSX were averaged. From these averaged values, a mean molar efficacy ± SD of 13.2 ± 3.4 % and 23.6 ± 10.3 % was found for DFO and DSX, respectively. Relative to DFO, in each patient an increase between 5.5 and 27.1 % was found for DSX (mean: 11.7 ± 7.3 %). Patients with a low efficacy on DFO also had a low molar efficacy on DSX and vice versa (e.g., 8.0 and 13.5 % versus 16.0 and 31.9 %). Compliance assessed from tablet count protocols was larger than 90% and did not change these data significantly. On a larger scale in highly compliant thalassemia patients, a molar efficacy of 17.6 ± 4.8 % was observed (Fischer et al: Brit J Haematol2003; 121: 938–48). In comparison to that reference value, the molar efficacy of DFO for this patient group was decreased. The reported molar efficacy of 27.9 ± 13.8 % for DSX obtained from biopsy results (Porter et al: Blood2005; 106(11): 755a) is only insignificantly higher than our value. In summary, we found deferasirox to be two times more efficient than deferoxamine on the same molar dose level, even for patients with a relatively low efficacy under both chelator treatment regimens.

RésuméLa Suisse est un petit pays ; elle comprend cinq universités ayant des chaires de psychiatrie. La faible superficie et la stabilité favorisent des études épidémiologiques, en particulier des études prospectives longitudinales et catamnestiques.Une première étude longitudinale a été réalisée à Lausanne. En 1975, a été effectué un sondage sur un échantillon de 300 enfants âgés de 9 ans, évaluant de façon détaillée : la santé, le développement du langage, le Q.I., la réussite scolaire et la personnalité. Cette enquête a révélé que 35 % des enfants étaient sans symptômes tandis que 26 % présentaient des difficultés psychiques importantes, surtout les garçons issus de familles socialement défavorisées.A Zurich, une étude longitudinale portant sur 6 315 hommes suivis de 19 à 31 ans, a concerné : les caractéristiques sociales, la consommation de tabac, d'alcool et de drogues et des traits de personnalité. Ce travail longitudinal fournira des informations sur les relations existant entre comportement, consommation de toxiques et traits de personnalité.Un autre projet a pour but l’étude de la personnalité prémorbide chez des individus qui ont présenté une schizophrénie ou une psychose maniaco-dépressive après l’âge de 19 ans, ainsi que chez tous les patients décédés accidentellement ou par suicide ;Un autre projet a pour but d'évaluer l’entraide du “voisinage” dans un quartier bien défini de Zurich ;1000 personnes seront ainsi suivies prospectivement pendant une période de 3 à 5 ans.A Genève, ont été enregistrés les dossiers de tous les malades traités dans les institutions psychiatriques (hospitalisations et prises en charge ambulatoires).A Bâle, une étude importante sur les troubles dépressifs des patients traités par des médecins généralistes a fourni des résultats très intéressants, surtout à propos de la fréquence des dépressions masquées.A Zurich, plusieurs études épidémiologiques ont porté sur des maladies psychiatriques infantiles, en particulier le trouble déficitaire de l'attention (“attention deficit disorder”), la dépression et l’encoprésie). Une étude multicentrique et longitudinale a montré une augmentation actuelle de l’incidence de l’anorexie mentale ;A Bâle, se déroule actuellement une étude longitudinale de 6 ans sur des toxicomanes (comparaison des résultats obtenus avec d’autres institutions qui prennent des toxicomanes en charge).Des études catamnéstiques comparent des toxicomanes avec d’autres groupes de malades pour évaluer (entre autres) le degré de dépendance dans cette population.Un questionnaire réalisé à Bâle sur les drogues et l’alcool présente un intérêt méthodologique remarquable.Des études cliniques plus traditionnelles gardent encore une place importante. A Lausanne, on étudie des démences séniles et d’Alzheimer chez les personnes âgées, dans le but de comparer des thérapeutiques différentes.A Genève, plusieurs éludes catamnestiques portent sur l'évolution des patients schizophréniques, en particulier suivis en ambulatoire.A Zurich, depuis 1959, on effectue tous les 5 ans une étude prospective pour étudier l’insertion sociale des malades mentaux.A Berne, sont étudiés les facteurs prognostiques chez les patients dépressifs et schizophrènes (famille, environnement).En ce qui concerne la médecine psychosomatique plusieurs projets ont trait aux réactions psychologiques des patients présentant une maladie chronique.En matière de psychopharmacologie tous les “centres” des villes universitaires participent à l'évaluation des nouveaux psychotropes, on relève cependant un manque d’études comprenant des contrôles “placebo”.A titre d'exemples, ont été étudiés : • les effets des perfusions de dibenzépine, de clomipramine et de maprotiline; • la réponse TRH comme élément éventuel de prédiction de la réponse aux antidépresseurs tricycliques (Bâle) ; • la corrélation des concentrations plasmatiques de maprotiline, d’amitriptyline et de nortriptyline avec l’efficacité clinique (Lausanne) ; • enfin, les vertus potentielles du L-tryptophane dans les troubles du sommeil font l'objet d’investigations actuelles.

Abstract Resistance to glucocorticoids (GC) is a hallmark of relapsed acute lymphoblastic leukemia (ALL) and is a predictor of outcome at diagnosis. In spite of the importance of GC in the treatment of ALL and other hematological malignancies the molecular mechanisms that lead to effective eradication of leukemic cells is incompletely understood. To address this problem we have performed a functional screen for genes involved in prednisolone resistance in ALL cell line (Reh) and correlated these results with our previously published results using an integrated genomic analysis to discover genes (pathways) altered at relapse (Hogan et al 2011). Cells were infected with a pooled whole genome shRNA library that contained approximately 80,000 shRNAs targeting 18,000 genes. Deep sequencing was used to identify shRNAs enriched or depleted upon treatment with prednisolone. Three computational methods including; bioinformatics for next generation sequencing analysis (BiNGS), redundancy & fold change analysis (RFC) and strict standardized mean difference (SSMD) were applied to the sequencing data in efforts to obtain the most robust set of candidate genes for validation (Porter et. al, Leukemia 2012, Zhang XD, J Biomol Screen, 2007). Through our primary screen a total of 263 genes were identified to modulate prednisolone sensitivity in ALL. Upon knockdown, 142 genes increased the sensitivity of the cells to prednisolone and 121 genes increased resistance to prednisolone. Five genes overlapped with genes previously identified to be altered at relapse compared to matched diagnosis samples including SLC6A18, AARSD1, MIER3, CDC42BPB, and YAP1. We hypothesize that genes that are altered at relapse in ALL and identified through functional genomics screening to modulate chemosensitivity in vitro, are likely drivers of chemoresistance and eventual relapse. We also performed gene ontology (GO) analysis using DAVID Bioinformatics to identify pathways that may be responsible for altered resistance to prednisolone. This analysis strongly implicated the mitogen-activated kinase (MAPK) pathway. The MAPK was also identified as a pathway with increased activity at relapse through our integrative genomics analysis(Hogan et al 2011). One gene of particular interest was MAP2K4 which encodes for MEK4, an upstream kinase involved in JNK phosphorylation and c-Jun activation. Knockdown of MAP2K4 by shRNA in B-precursor ALL cell lines (Reh and RS4;11) results in statistically significant (p-value < 0.5) increased sensitivity to prednisolone induced apoptosis at a range of prednisolone concentrations but not to other chemotherapy tested (etoposide, doxorubicin, and 6-thioguanine).604. Molecular Pharmacology, Drug Resistance: Poster I Upon treatment with prednisolone MAP2K4 knockdown cells have increased levels of prednisolone responsive genes GILZ (1.4-2.4 fold in Reh, 2.1-3.8 fold in RS4;11) and TXNIP (1.8-5.7 fold in Reh, 2.5-2.6 in RS4;11). Increased sensitivity to prednisolone and increased levels of prednisolone responsive genes was associated with decreased levels of p-JNK that has been previously implicated in regulating glucocorticoid signaling through phosphorylation of the glucocorticoid receptor (GR) at S226 (Roatsky et. al, PNAS 1998, Itoh et. al, Mol. Endo. 2002).s Overall this data suggests that decreased levels of MAP2K4 results in increased sensitivity to GC by increasing GC signaling and implicates MEK4 as novel drug target in ALL. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4274 Background: While iron overload is known to cause hepatic toxicity, the effect of iron chelation therapy on liver pathology is not well understood. Data evaluating liver fibrosis during iron chelation therapy are limited to small studies (eg, Wu SF et al. Hemoglobin 2006 [n=17], Berdoukas V et al. Hematol J 2005 [n=49], Wanless IR et al. Blood 2002 [n=56]). In order to address such effects in a more robust patient population, we assessed liver biopsy samples from β-thalassemia patients enrolled in two large clinical studies (Porter J et al. Blood 2005, Cappellini MD et al. Blood 2006) that evaluated the effects of deferasirox on iron burden for up to 5 years. Methods: Patients with β-thalassemia and transfusional hemosiderosis receiving ≥8 blood transfusions/year, with liver biopsy assessment (defined as having either liver iron concentration [LIC], Ishak grading or Ishak staging assessment), after at least 3 years of deferasirox treatment, were included. Deferasirox dose was 5–40 mg/kg/day based upon level of iron overload (Study 107, patients randomized to deferoxamine [DFO] or deferasirox for the first year; Study 108, patients received deferasirox only). Treatment response success was defined according to baseline (start of deferasirox dosing) and end-of-study (EOS) LIC measurements (Table). Histological total iron score (TIS) was derived from the iron load observed in hepatocytes (hepatocytic iron score [HIS] range, 0–12), sinusoidal cells (sinusoidal iron score [SIS] range, 0–4) and main structures of the portal tracts (portal iron score [PIS]). A heterogeneity factor (H = 1, 2 or 3) was then applied, based on the overall appearance of the tissue, to provide TIS, calculated as (HIS + SIS + PIS) × (H/3) [range 0–60]. Hepatocytic to total liver iron ratio was calculated as HIS/(HIS + SIS + PIS) (Deugnier Y et al. Gastroenterol 1992). Fibrosis staging was performed according to Ishak scale from 0 (no fibrosis) to 6 (cirrhosis, probable or definite). Liver inflammation was assessed according to the Ishak necroinflammatory grading system with an overall scoring range from 0–18 (Ishak K et al. J Hepatology 1995). Results: Of 770 patients enrolled in the deferasirox studies, 219 with histological biopsy data at baseline and at the end of at least 3 years of treatment with deferasirox were eligible for analyses. Mean LIC was 15.7 ± 9.9 mg Fe/g dw and median serum ferritin was 2069 ng/mL (range 273–11698) at the start of deferasirox treatment. After at least 3 years of treatment, overall LIC success response rate was 63.8% (n=134), and mean LIC decreased by 5.5 ± 10.6 to 10.1 ± 8.2 mg Fe/g dw. Mean absolute change in TIS and liver iron ratio were -8.2 ± 13.3 and -2.1 ± 27.3, respectively. The range of Ishak necroinflammatory scores at baseline was 0–8 with a mean of 2.0 (2.2 in patients who met success rate criteria [Group A], 1.6 in patients who did not meet the success rate criteria [Group B]). At EOS the necroinflammatory score improved to a mean of 0.8 overall, and in both subgroups, with a mean relative change of -66% (69% in Group A and -61% in Group B). Overall 83.3% (n=175) [85.8% (n=115) in Group A, 78.9% (n=60) in Group B] of patients experienced either stabilization or improvement in their Ishak fibrosis score. Ishak staging remained stable (change of -1, 0 or +1) in 55.7% (n=122) of patients. Fifty-nine patients (26.9%) had an improvement in Ishak grading by a score of ≥2. Similar improvements were observed between Group A (26.1%, n=35) and Group B (30.3%, n=23). Conclusions: This is the first study to assess the effect of iron chelation therapy on liver pathology in a large cohort of iron-overloaded patients with β-thalassemia. In addition to reducing total iron burden, deferasirox led to an improvement in pathological markers of iron overload-induced liver damage in the majority of patients; 83.3% showed stabilization or improvement in Ishak fibrosis staging as well as an overall improvement in necroinflammatory score. These effects were similar in both patients who met the LIC success rate criteria and those who did not, suggesting that the observed effects may be at least partly independent of the drug's chelation effect. These findings are important as stabilization or regression of hepatic fibrosis in the face of chronic insult may prevent progressive liver disease. Disclosures: Deugnier: Novartis: Honoraria. Dong:Novartis: Employment. Giannone:Novartis: Employment. Zhang:Novartis: Employment. Griffel:Novartis: Employment. Brissot:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Abstract Background Patients with myocardial iron overload require effective cardiac iron removal to minimize the risk of cardiac complications. The 3 year EPIC cardiac sub-study showed that the oral iron chelator, deferasirox (DFX), effectively reduced cardiac iron overload. Previous reports demonstrate that cardiac iron removal is slow and suggest that liver iron concentration (LIC) may affect cardiac iron removal rate by chelators (Pennell et al., 2012; Blood). The objective of these analyses was to evaluate the impact of the severity of the liver iron overload on the change in myocardial T2* (mT2*) for patients receiving up to 3 years of DFX treatment in the EPIC sub-study. Methods Inclusion and exclusion criteria have been described previously (Pennell et al., 2012; Haematologica). Patients were categorized into LIC ≤15 and >15 mg Fe/g dry weight (hereafter mg/g) at baseline (BL) and by LIC <7, 7–≤15 and >15 mg/g at 12, 24, and 36 months to assess the impact of BL LIC and changes in LIC overtime on mT2*, respectively. During study, LIC and mT2* were measured every 6 months. Efficacy was assessed in per-protocol population that entered third year extension. Here, mT2* is presented as the geometric mean (Gmean) ± coefficient of variation (CV) unless otherwise specified. Statistical significance was established at α-level of 0.05 using a 2-sided paired t-test for within group comparisons and ANOVA for multiple group comparisons. All p-values were of exploratory nature for this post-hoc analysis. Results Of the 71 patients, who continued into study year 3, 68 patients considered evaluable were included in this analysis (per protocol population); 59 patients had LIC values available at end of study (EOS). Mean age was 20.5 ±7.35 years and 61.8 % of patients were female. Mean actual dose of DFX (mg/kg/day) was 32.1 ±5.5 and 35.1 ±4.9 in patients with BL LIC ≤15 and >15 mg/g, respectively. At EOS, mean actual doses were 32.9 ±5.4 (LIC <7 mg/g), 38.0 ±3.4 (LIC 7–≤15 mg/g), and 37.6 ±3.1 (LIC >15 mg/g). Overall, patients had high BL LIC (Mean, 29.0 ±10.0 mg/g); 61 patients had LIC >15 (30.8 ±8.8) mg/g, only 7 patients had LIC ≤15 (12.7 ±1.1) mg/g, and no patients had LIC <7 mg/g. After 36 months, a significant mean decrease from BL in LIC of -7.6 ±4.6 mg/g (p = 0.0049) and -16.8 ±14.0 mg/g (p <0.001) was observed in patients with LIC ≤15 and >15 mg/g, respectively. Notably, 51.9% of patients with BL LIC >15 mg/g achieved EOS LIC <7 mg/g. Overall, mean mT2* was 12.8 ±4.6 ms. The impact of BL LIC on mT2* and LIC response was as follows: in patients with LIC ≤15 mg/g (Mean BL mT2*, 14.2 ±3.6 ms) and >15 mg/g (BL mT2*, 12.7 ±4.7 ms), mT2* increased by 52% (Mean abs. change, 7.5 ±4.1 ms, p=0.0016) and 46% (7.3 ±7.3 ms, p<0.001), respectively. Patients with BL LIC ≤15 normalized mT2* in 24 months (Mean, 20.0 ±6.0 ms) versus 36 months for patients with BL LIC >15 mg/g, (20.1 ±10.6 ms) displaying a lag of nearly 12 months. The relation between post-BL LIC on mT2* response at 12, 24 and 36 months is shown in the figure. At 12 months, there was no significant difference in mT2* that had occurred in patients with LIC <7 mg/g (24% increase; mean abs. change, 3.5 ±2.3 ms), LIC 7–≤15 mg/g (19% increase; 3.4 ±5.2 ms) and those with LIC >15 mg/g (13% increase; 1.9 ±3.2 ms). However, at 24 months, there was a statistically significant difference amongst the 3 subgroups in percent increase in the mT2* that had occurred; patients with LIC <7, LIC 7-≤15 and LIC >15 mg/g had 54% (Mean abs. change, 8.3 ±7.3 ms), 33% (5.2 ±5.2 ms) and 10% (2.1 ±4.3 ms) increase (p <0.001), respectively. Similarly, at 36 months, the mT2* had increased by 71% (Mean abs. change, 10.3 ±6.6 ms) in the LIC <7 mg/g group; a 31% increase (5.3 ±5.0 ms) had occurred in the LIC 7– ≤15 mg/g group; and an 18% (3.3 ±6.0 ms) increase (p <0.001) had occurred in the LIC >15mg/g group. At all-time points, in patients who achieved an LIC <7 mg/g, a statistically significant increase in T2* from BL had occurred. Discussion Overall, DFX treatment resulted in a significant decrease in LIC and improved mT2*. A greater difference in mT2* improvement was shown to have occurred in patients who achieved lower end-of-year LIC after treated with DFX. This divergence was progressive with time, being maximal at 36 months. Thus, a therapeutic response in LIC with DFX is associated with a greater likelihood of improving mT2*. This may assist in monitoring liver and cardiac response to DFX. Prospective evaluation of this relationship is indicated. Disclosures: Porter: Novartis Pharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Taher:Novartis Pharma: Honoraria, Research Funding. Aydinok:Novartis Oncology: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cappellini:Novartis Pharma: Honoraria, Speakers Bureau; Genzyme: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. El-Ali:Novartis Pharma: Employment. Martin:Novartis Pharma: Employment. Pennell:Novartis: Consultancy, Honoraria, Research Funding; ApoPharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria.

Introduction: BELIEVE is an ongoing phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, in adults with β-thalassemia requiring regular RBC transfusions (ClinicalTrials.gov identifier: NCT02604433). Treatment with luspatercept significantly reduced RBC transfusion burden and was associated with a favorable safety profile in this patient (pt) population (Piga A, et al. Blood. 2019;133:1279-89). Here we report iron-related efficacy endpoints of the BELIEVE study, including change from baseline in serum ferritin, liver iron concentration (LIC), and myocardial iron, as determined by T2*-weighted magnetic resonance imaging (MRI), and the effect of baseline iron levels on response to luspatercept. Methods: Adults with β-thalassemia or hemoglobin (Hb) E/β-thalassemia who required regular transfusions of 6-20 RBC units in the 24 weeks (wks) prior to randomization (with no transfusion-free period ≥ 35 days during that period) were randomized 2:1 to luspatercept (starting dose level 1.0 mg/kg; titration up to 1.25 mg/kg) or placebo, administered subcutaneously every 3 wks for ≥ 48 wks. Pts in both arms could receive RBC transfusions and iron chelation therapy (ICT) throughout the study to maintain their baseline Hb levels. Results: 332/336 randomized pts received treatment with luspatercept or placebo; 209/223 (93.7%) and 104/109 (95.4%) pts in the luspatercept and placebo arms had history of iron overload, defined as serum ferritin > 1,000 µg/L or LIC > 7 mg/g dry weight. 97.3% of luspatercept-treated and 97.2% of placebo-treated pts received ICT at baseline; 62.3%, 41.3%, and 37.2% received deferasirox, deferiprone, and deferoxamine, respectively, in the luspatercept arm, vs 57.8%, 36.7%, and 35.8% in the placebo arm. Fewer pts received ICT as combination therapy vs monotherapy (luspatercept arm: 28.6% vs 68.8%; placebo arm: 24.1% vs 72.3%, respectively). Mean baseline serum ferritin, LIC, and myocardial iron (by T2* MRI) for luspatercept vs placebo arms were 2,096.91 vs 1,845.05 μg/L, 12.04 vs 10.09 mg/g, and 33.52 vs 34.76 ms, respectively. As of Jan 7, 2019, 157 (70.4%) continue to receive luspatercept and 92 (84.4%) crossed over from the placebo arm. During the last 12 wks of the 48-wk randomized treatment period, mean change from baseline in serum ferritin was −248.02 μg/L vs +106.62 μg/L for pts in the luspatercept and placebo arms, respectively (least squares mean [LSM] difference: −347.80; P < 0.0001). 158/224 (70.5%) and 33/112 (29.5%) pts in the luspatercept and placebo treatment arms achieved a ≥ 33% reduction in RBC transfusion burden of ≥ 2 RBC units during any 12-wk interval. Among the responders, mean change from baseline in serum ferritin was −343.22 μg/L and +47.30 μg/L for pts receiving luspatercept and placebo, respectively (LSM difference: −389.50; P = 0.0047). Of 140 luspatercept-treated pts with baseline ferritin ≥ 1,000 μg/L, 29 (20.7%) achieved post baseline ferritin of < 1,000 μg/L when assessed over the entire treatment period; results were similar in responders and non-responders. During the treatment phase, mean change in myocardial MRI iron signal (T2*) from baseline to Wk 48 was −1.83 ms for luspatercept and +0.02 ms for placebo (LSM difference: −2.39; P = 0.0391). Over 96 wks, 6 (20%) luspatercept-treated pts with baseline myocardial iron ≤ 20 ms had post-baseline results > 20 ms; results were similar between responders and non-responders. Mean LIC changes from baseline to Wk 48 (mg/g dry weight) were +0.10 and +0.08 for luspatercept and placebo arms, respectively (LSM difference: +0.11; P = 0.8685). Over 96 wks, mean change in LIC among luspatercept-treated patients overall was −0.5 mg/g and −1.1 mg/g among responders. When assessing impact of baseline iron loading there was a general consistency in achievement of ≥ 33% reduction in RBC transfusion with luspatercept over any 12 wks, regardless of iron loading subgroup (baseline serum ferritin, LIC, and myocardial iron) (Table). Conclusions: Luspatercept treatment resulted in clinically meaningful reductions in serum ferritin levels. Baseline iron overload did not seem to affect response to luspatercept; treatment resulted in clinically meaningful reductions in RBC transfusion burden regardless of baseline serum ferritin level, LIC, or myocardial iron loading. Disclosures Porter: Celgene Corporation: Consultancy, Honoraria; Protagonist: Honoraria; Vifor: Honoraria; La Jolla: Honoraria; Agios: Consultancy, Honoraria; Silence Therapeutics: Honoraria; Bluebird Bio: Consultancy, Honoraria. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Coates:apo pharma: Consultancy, Honoraria, Speakers Bureau; agios pharma: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study; vifor: Consultancy, Honoraria. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Novartis: Research Funding; Celgene: Research Funding. Viprakasit:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding; Vifor: Consultancy, Research Funding; Ionis: Consultancy, Research Funding; La Jolla: Consultancy, Research Funding. Voskaridou:Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Perrotta:Acceleron Pharma: Research Funding; Novartis: Honoraria, Research Funding. Kattamis:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Shetty:Celgene Corporation: Employment, Equity Ownership. Kuo:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene International: Employment. Zinger:Celgene Corporation: Employment. Linde:Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership; Abbott Laboratories, Inc.: Equity Ownership. Sinsimer:Celgene Corporation: Employment, Equity Ownership. Taher:Protagonist Therapeutics: Consultancy, Research Funding; La Jolla Pharmaceuticals: Consultancy, Research Funding; Celgene Corporation: Research Funding; Abfero: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Ionis Pharmaceuticals: Consultancy. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Abstract Introduction: The PTCL appear to be exquisitely sensitive to epigenetic modifiers, including histone deacetylase inhibitors and hypomethylating agents. While the PTCL harbor recurring mutations in genes controlling CpG methylation, including TET2, IDH2 and DNMT3, it is not clear these genetic events portend sensitivity to these classes of drugs. In preclinical models of PTCL, HDACi and HMA exhibit marked class synergy in vivo and in vitro. Early Phase 1 and 2 experiences have confirmed compelling activity across the PTCL, with exceptionally high response rates in patients with angioimmunoblastic T-cell lymphoma. While the precise mechanism of synergy is under investigation, it is clear these drugs can induce a host of immunological effects on both the tumor cell proper as well as the host. We present details of these class effects in models of PTCL. Methods: We have explored combinations of azacitidine and romidepsin in a panel of 6 TCL cell lines. The cell viability was accessed and synergy was calculated using Excess Over Bliss modeling to determine the efficacy of the combination. We then performed RNAseq analysis on 4 TCL lines. We confirmed the protein expression of multiple targets using western blot to confirm to results obtained from sequencing. TCL lines were exposed to combination for 96 hours, supernatant was collected and assayed for proliferative properties using isolated PBMCs from healthy donors and anti-CD3/anti-CD28 beads. Results: The combination of azacitidine and romidepsin were potently synergic across all 6 cell lines. Determination of DNA methylation revealed a decrease in %MdC, as a function of concentration. A supervised analysis of the RNAseq revealed almost all of the genes perturbed by the single agent treatments were enhanced by the combination. There were 1215 genes affected by combination treatment with a p-value ≤0.05; 921 of the genes were not found in either single agent cohort. Of the 1215 genes, 936 were upregulated and 279 genes were downregulated. A gene set enrichment analysis (GSEA) of the RNAseq data displayed a significant down regulation in multiple genes involved in cholesterol biosynthesis in the combination, for example, HMGCR (-2.1 FC), FDPS (-2 FC) and IDI1 (-1.8 FC). The RNAseq analysis revealed a marked increase in expression levels in a variety cancer/testis antigens (CTA) that were most amplified by the combination, such as PRAME (4.9 FC) and MAGE-A1 (11.3 FC). As single agents, azacitidine alone was capable of inducing minor expression of some targets while romidepsin did not affect any. There was a radical change in genes involved in viral/interferon response and immune response observed in RNAseq. The expression of a handful of interleukins and interferons associated with viral/interferon and immune responses were induced by single agent azacitidine and amplified the most by the combination, such as IF16 (1.4 FC aza, 2.8 FC combo), IL18 (3.4 FC combo), IL34 (2.4 FC aza, 3.7 FC combo) and IL26 (5.2 combo FC). Noticeably, single agent romidepsin (3 FC) and the combination (6 FC) augmented the expression of CD274 (PD-L1).Most drastically intensified from this subset of immune response genes was TBX21 (6.9 FC) expression that was induced by the combination. We see from a western blot that the combination induces maximum protein expression levels of T-bet (transcription factor encoded by TBX21) in 4/6 TCL cell lines. STAT4, known to interact with T-bet to promote Th1-differentiation, protein expression was confirmed to increase with combination treatment in 4/6 TCL cell lines. Enhanced proliferation was seen when PBMCs were cultured with conditioned medium from 4 different TCL lines treated with the combination. Conclusions: The generated data presents a strong justification for the use of combination in addition to an immune checkpoint inhibitor, such as a PD-1/PD-L1 inhibitor. With the emergence of members of CTA family becoming a developing marker in immunotherapy, it is of absolute importance to narrow down the possible targets induced by combination therapy. Here we identify two members of the family that are uniquely expressed as a result from exposure to the combination. Interestingly, the combination is also able to induce a Th1-like phenotype that is often associated with a favorable prognosis. These data suggest that azacitidine and romidepsin in TCL is a promising platform treatment that undeniably proves itself advantageous in preclinical models. Disclosures O'Connor: Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Celgene: Research Funding.

Abstract Abstract 2126 Background: In patients with transfusion-dependent anemias, monitoring the efficacy of iron chelation therapy (ICT) using serum ferritin (SF) alone can sometimes be challenging; therefore, additional serum markers would be helpful. Furthermore, any differences between different anemias for the relationship between SF and other serum markers both before and in response to ICT may be useful to predict relative risk of iron-mediated toxicity between these conditions. Data from the 1-yr EPIC (Evaluation of Patients' Iron Chelation with Exjade®) trial allows assessment of iron parameters in a large cohort of patients with thalassemia, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Here we evaluate trends in liver iron concentration (LIC), transferrin saturation (TfSat) and labile plasma iron (LPI) in their relation to SF levels and assess systematic differences between underlying anemias. Relationships were assessed at baseline (BL), reflecting iron accumulation at study entry, and also at end of study (EOS), with changes reflecting iron excretion after 1 yr treatment with deferasirox. Methods: LIC, TfSat and LPI were measured at BL and at EOS for each underlying disease. Changes in these parameters as well as relationships between these parameters and SF were assessed by SF categories at BL and at EOS. For EOS measurements, last observation carried forward was used for all parameters (last post-BL available value), except for LPI, for which 1-yr visit was used. Pre-deferasirox dose LPI levels are reported. Results: Data from 1114 thalassemia patients, 336 MDS patients and 80 SCD patients were available for analysis. For all underlying anemias, LIC was higher at higher SF categories; in thalassemia patients for eg, with BL SF categories <1000, 1000–2000, 2000–3000, 3000–4000, 4000–5000, >5000 ng/mL, the mean LIC values at BL were 4.9, 9.0, 15.3, 22.1, 27.2, 32.5 mg Fe/g dw, respectively. Overall, mean TfSat was 89.6% (n=755) in thalassemia patients at BL and 96.1% (n=955) at EOS, compared with 82.5% (n=116) and 83.8% (n=171) in MDS patients, respectively. In SCD patients, TfSat was 61.3% (n=71) at BL and 64.1% (n=74) at EOS. TfSat was lowest in SCD patients across the full range of SF categories examined (Figure). At BL, TfSat was higher at higher SF categories in all diseases, with a similar trend at EOS, although at EOS this trend was more evident in MDS and SCD (Figure). Overall, mean LPI levels at BL and EOS were 1.25 μmol/L (n=472) and 0.59 μmol/L (n=818) in thalassemia patients, 0.53 μmol/L (n=221) and 0.14 μmol/L (n=147) in MDS patients, and 0.11 μmol/L (n=55) and 0.10 μmol/L (n=46) in SCD patients, respectively. LPI levels were highest in patients with thalassemia and lowest in SCD patients across SF categories (Figure). After 1 yr treatment with deferasirox, LPI levels were reduced in thalassemia and MDS patients, but there was no difference in patients with SCD. LPI was higher at higher SF categories in MDS patients at both BL and EOS, with a similar trend in SCD patients at EOS, although there was little relationship in thalassemia patients (Figure). Discussion: At matched SF levels and across a wide range of SF values, TfSat was lower in SCD patients, in comparison to thalassemia and MDS patients, both at BL and EOS. Similar observations have been reported previously and may contribute to the lower propensity for extra-hepatic iron accumulation in SCD patients. The mechanisms for this difference remain unclear, but could be attributed to sequestering of iron due to chronic inflammation in SCD. TfSat did not appear to decrease after 1 yr treatment with deferasirox, in any underlying anemia. The relationship of LPI to SF categories differed between underlying anemias; both at BL and EOS. At BL, SCD patients had low LPI values across the full range of measured SF values, whereas higher LPI levels at higher SF categories were most evident in MDS patients. Overall, LPI was highest in thalassemia patients. After 1 yr treatment with deferasirox, LPI was decreased in thalassemia and to a lesser extent in MDS patients, but there was no change from the low level at BL in SCD patients. The decrease in LPI in MDS and thalassemia at EOS may reflect the effects of residual plasma chelator 1 day after the previous dose and/or the decrease in storage iron over 1 yr of treatment. With further evaluation, LPI could become a useful marker of iron overload and chelation response in patients with MDS and possibly thalassemia. Disclosures: Porter: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Viprakasit:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Martin:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.

Une expertise scientifique collective conduite par l’Inra (INRA 2012) pointe l’importance des flux d’azote liés aux activités d’élevage et identifie des leviers pour limiter la pression sur l’environnement. Depuis une vingtaine d’années, les pollutions azotées font l’objet de diverses législations et plans d’action dans le cadre des politiques relatives à la qualité des eaux, de l’air et des écosystèmes. La transposition de la directive «Nitrates» (12 décembre 1991) fait actuellement l’objet d’un contentieux avec la commission européenne. C’est dans ce contexte que les ministères français en charge de l’Agriculture et de l’Ecologie ont sollicité l’Inra pour dresser un bilan de l’état des connaissances scientifiques sur les flux d’azote en élevage et leur devenir. L’objectif était de mettre à disposition des décideurs et des acteurs publics et privés les connaissances scientifiques actualisées et d’identifier des options permettant de réduire les pressions de l’azote sur l’environnement. 1/LA MÉTHODE D’EXPERTISE SCIENTIFIQUE COLLECTIVELe travail d’expertise a été porté par un collectif de 22 experts. Deux tiers d’entre eux appartiennent à l’Inra, un tiers à d’autres organismes de recherche (Irstea, CNRS, universités) dont deux experts des Pays-Bas (WUR) et un du Canada (Agriculture et Agroalimentaire Canada). Les sciences sociales ont fourni un quart de l’effectif d’experts, la zootechnie et l’approche systémique des systèmes d’élevage 40% et le complément regroupe des spécialistes des cycles biogéochimiques et de l’agronomie. La méthode a consisté à dresser un état des lieux critique des connaissances scientifiques publiées. Quelque 1360 références bibliographiques (2900 auteurs) ont été sélectionnées parmi les articles les plus récents (80% des sources sont postérieures à 1998) et relatifs ou transposables au cadre géographique français. L’analyse a privilégié l’échelle de l’exploitation agricole car c’est l’unité de référence des politiques agricoles et environnementales et des actions agronomiques. Cependant les informations scientifiques portent souvent sur un niveau infra : l’animal, l’atelier d’élevage, la parcelle, le bâtiment, la zone de stockage, etc., ou sur un niveau supra : le bassin versant, le paysage, les statistiques et modélisations nationales et internationales. Ces différents niveaux d’information ont permis d’approcher les variations entre productions et celles liées aux pratiques agricoles. 2 / L’EXPERTISE A MIS EN AVANT LE RÔLE MAJEUR DE L’ÉLEVAGE DANS LES FLUX D’AZOTE ET LES IMPACTS POTENTIELS 2.1 / Les flux d’azote en élevage et les fuites vers l’environnement sont élevésL’élevage utilise plus des trois quarts des quantités d’azote entrant dans les systèmes agricoles. Mais l’efficience, c’est-à-dire le rapport entre les sorties valorisées et les entrées d’azote, calculée au niveau de l’animal est globalement faible : souvent beaucoup moins de la moitié de l’azote ingéré se retrouve sous forme de protéines consommables, lait, œufs et viande. A l’échelle de l’exploitation d’élevage, une part de l’azote excrété dans les déjections est recyclée avec les effluents mais l’efficience reste néanmoins généralement inférieure à 50%. Le reste de l’azote se disperse dans l’environnement. L’élevage contribue ainsi pour environ la moitié aux pertes nationales de nitrates vers les eaux, et pour plus des trois quarts aux émissions nationales atmosphériques azotées, notamment sous forme d’ammoniac (et jusqu’à 90% si on tient compte du fait qu’une grande partie des engrais industriels est employée sur les cultures utilisées pour produire des aliments du bétail). L’azote se trouve de ce fait à la croisée de préoccupations croissantes en termes de compétitivité des filières animales et d’impacts sur l’environnement et sur la santé humaine. Ces impacts ont été récemment décrits dans une expertise européenne (European Nitrogen Assessment 2011). Ils interviennent au niveau de l’écosystème environnant (dépôts de NH3), de la région (NH3, NO3 -) et plus globalement dans le changement climatique (émissions de N2O). 2.2 / La question de l’azote ne se réduit pas à celles du nitrate, les émissions de NH3 constituent un enjeu fort Alors qu’en France, la question du nitrate a longtemps focalisé les débats, dans certains pays d’Europe du Nord, l’ammoniacest aussi de longue date au centre des préoccupations. D’abord étudié pour son rôle dans l’acidification et l’eutrophisation des milieux, l’ammoniac est aujourd’hui examiné dans le cadre de la pollution de l’air par les particules. Au niveau national, le premier contributeur d’émissions d’ammoniac est l’élevage bovin. 2.3 / Risques et impacts dépendent aussi de la sensibilité des territoires et de leur capacité d’épurationLes teneurs en nitrate des eaux ne dépendent pas seulement du niveau de surplus des bilans azotés mais aussi du climat, des types de sol, de la topographie et des modes d’occupation des sols : densité animale, part des terres agricoles dans les utilisations totales des surfaces, importance des prairies permanentes, etc. La présence majoritaire de prairies au sein des territoires réduit les risques de fuites de nitrate et d’émissions d’ammoniac. 3/LES FLUX D’AZOTE SONT AUSSI DÉTERMINÉS PAR DES CONSIDÉRATIONS ÉCONOMIQUES ET JURIDIQUES3.1 / La concentration spatiale des élevages a un rôle déterminant dans les impacts des pollutions azotéesLes plus fortes pressions azotées se situent dans les territoires de l’Ouest qui combinent productions de ruminants et de monogastriques. Les quantités d’azote contenues dans les effluents y dépassent parfois largement les capacités d’absorption des surfaces agricoles. Les territoires d’élevage plus extensifs connaissent des pressions azotées faibles. Cette hétérogénéité s’explique par la concentration géographique des filières animales, résultant principalement de facteurs économiques dont les moteurs relèvent des économies d’échelle et des économies d’agglomération qui sont liées à l’intensification et à la spécialisation des élevages ainsi qu’à leur concentration territoriale. La littérature scientifique pointe la difficulté de sortir d’une telle trajectoire, notamment parce que le fonctionnement technique et économique des acteurs des filières (producteurs d’intrants, éleveurs, transformateurs) est étroitement dépendant. 3.2 / L’encadrement juridique n’a pas permis d’atteindre les objectifs environnementaux La réglementation française a abouti à une multiplicité de zonages auxquels sont dédiés des normes, obligations ou programmes d’action volontaire. L’architecture d’ensemble est confuse et ses résultats critiqués de longue date. Parmi les difficultés rencontrées, la littérature pointe i) le caractère diffus des pollutions, qui, à la différence d’autres pays, n’a pas incité en France àune responsabilisation individuelle des éleveurs, ii) l’intégration de préoccupations économiques et sociales dans les politiques environnementales, iii) le suivi des objectifs environnementaux confié aux acteurs du développement agricole et les échelles administratives peu pertinentes vis-à-vis du réseau hydrographique. Enfin, la multiplicité des formes de pollution azotée pose la question de la cohérence d’ensemble des politiques, notamment entre les critères de la directive «Nitrates» et ceux la Convention de Genève sur la pollution atmosphérique (1979). 4/DE NOMBREUSES PISTES DE PROGRÈS EXISTENT QUI ENGAGENT PLUS OU MOINS EXPLOITANTS AGRICO- LES, TERRITOIRES ET FILIÈRES D’ÉLEVAGE4.1 / Améliorer les pratiques à l’échelle de l’exploitationLa littérature fournit de nombreuses pistes d’actions pour limiter les pertes d’azote dans l’exploitation (figure 1). Il est encore possible d’optimiser la nutrition azotée des animaux, cependant les gains escomptés sont modestes en regard des enjeux. La maîtrise de la chaîne de gestion des effluents ouvre plus de marges de manœuvre pour préserver l’azote organique et réduire les achats d’engrais minéraux. En effet, selon les modalités de gestion des effluents, les fuites vers l’environnement varient de 30 à 75% de l’azote rejeté par les animaux. Des innovations sont déjà disponibles pour le stockage et l’épandage, même si les incertitudes sur les facteurs de variation des émissions sont encore grandes. Il est enfin démontré que développer les prairies à base de légumineuses, les cultures intermédiaires pièges à nitrate (Cipan) et ajuster les rotations réduit les risques de lixiviation du nitrate. A l’échelle des systèmes, les modes de production à bas intrants (moins de fertilisants et d’aliments riches en protéines) améliorent l’efficience de l’azote et limitent donc les pertes vers l’environnement. Les indicateurs de type bilan d’azote à l’échelle de l’exploitation et de ses sous-systèmes (troupeau, gestion des effluents, sols et cultures) sont des outils adaptés pour identifier les sources d’inefficacité et rechercher les voies d’amélioration les mieux adaptées localement. De nombreux autres indicateurs approchent les niveaux d’émissions, de pollution ou les impacts, mais ne sont pas toujours d’usage facile. pour le document complet voir le pdf https://www6.inrae.fr/productions-animales/content/download/6365/88149/version/1/file/nouvelles+de+la+recherche.pdf

Abstract Background Transfusion-dependent patients with severe cardiac siderosis often require intensive iron chelation therapy for a limited time to facilitate rapid removal of iron from the heart, allowing patients to move from a high-risk (cardiac T2*<10 ms) to lower risk (≥10 ms) status for heart failure. Oral deferasirox (DFX) monotherapy has been shown to improve cardiac T2*, but data on the combined use of DFX and deferoxamine (DFO) are limited. Aim To evaluate efficacy and safety of investigational DFX–DFO in combination followed by DFX monotherapy in patients with severe transfusional cardiac siderosis. Methods The prospective, Phase II, open-label, multinational HYPERION study evaluated DFX–DFO in combination followed by DFX monotherapy in transfusion-dependent patients with severe cardiac siderosis (NCT01254227). Patients enrolled were ≥10 years with CMR-measured cardiac T2* 5–<10 ms, left ventricular ejection fraction (LVEF) ≥56%, R2-MRI liver iron concentration (LIC) ≥7 mg Fe/g dw. Starting dose was DFX 20 mg/kg/d, 7 d/wk, plus DFO 40 mg/kg/d, 5 d/wk for ≥8 hrs/d. DFX dose could be increased to 30 and 40 mg/kg/d after Month 1 and 6, respectively. Patients achieving cardiac T2* ≥10 ms and a relative T2* increase of ≥10% from baseline (BL) any time after 6 months were switched to DFX monotherapy. Combination therapy was resumed if cardiac T2* fell to <10 ms with a relative decrease of ≥10% from previous T2* value. Dose adjustments were based on efficacy and safety parameters. Primary efficacy endpoint was change in geometric mean cardiac T2* at Month 12 divided by that at BL. A key secondary objective was the proportion of patients achieving T2* ≥10 ms and a ≥10% relative increase from BL after 6 and 12 months. Efficacy was analyzed for all evaluable patients in the full analysis set (FAS) who received ≥1 dose of study drug and had a BL and post-BL assessment; cardiac T2* is also reported for patients with T2* at BL and Month 12 (12-month completers). Results 60 patients were enrolled (59 β-thalassemia major, 1 Diamond–Blackfan anemia; mean age 22.8 years; 46.7% male) with severe iron overload (geometric mean [Gmean] cardiac T2* 7.03 ms, mean LIC 33.4 ± 14.5 mg Fe/g dw, median serum ferritin 5551 ng/mL [range 1163, 11,317]). Overall, 20 patients discontinued; 5 consent withdrawals, 4 adverse events (AEs: pruritus, arthritis, abdominal pain, drug rash with eosinophilia and systemic symptoms), 4 abnormal test procedure results (all T2* <5 ms), 4 lost to follow-up, 2 administrative problems, 1 death (central nervous system infection, suspected relationship to DFO). Mean dose was DFX 29.6 ± 6.3, 7 d/wk, and DFO 37.4 ± 5.8 mg/kg/d, 5 d/wk. In the evaluable FAS (n=52, last observation carried forward) cardiac T2* increased 9% and LIC decreased 46% (Fig); serum ferritin levels decreased by 2174 ng/mL (–6138, 1570). Among 12-month completers (n=36), cardiac T2* increased from 7.24 at BL to 8.24 ms (14% improvement). In patients with BL LIC <30 and ≥30 mg Fe/g dw, cardiac T2* improvement was 17% (7.85 to 9.15 ms, n=16) and 6% (6.69 to 7.11 ms, n=36), respectively. Overall, 12.5 and 19.2% of patients achieved T2* ≥10 ms and ≥10% relative increase from BL at Month 6 and 12, respectively. Mean LVEF remained stable and no patient had cardiac failure. AEs with suspected relationship to study drug (≥5%) were abdominal pain, nausea (both 6.7%); increased blood creatinine, diarrhea, increased urine protein/creatinine ratio (all 5.0%). 1 patient had serum creatinine >33% increase from BL and >upper limit of normal at 2 consecutive visits. Discussion Cardiac T2* improved during 12 months of treatment with DFX–DFO in patients with severe transfusional body iron burden. High BL LIC levels decreased considerably with DFX–DFO. Overall, as LIC decreased cardiac T2* increased, most notably after 6 months. The higher DFX dose permitted after Month 6 possibly influenced this trend. Cardiac T2* improvements were observed irrespective of BL LIC value, but were most marked in those with BL LIC <30 mg Fe/g dw, consistent with previous data showing that cardiac iron removal follows liver iron removal (Noetzli Blood 2008). Safety of DFX–DFO was consistent with established monotherapy profiles, with no unexpected findings. 2-year follow-up for HYPERION will evaluate the impact of longer-term DFX–DFO in combination on liver and cardiac iron removal. Disclosures: Aydinok: Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Deferasirox and deferoxamine are both indicated as a monotherapy for the treatment of chronic iron overload due to frequent blood transfusions. Patients with severe cardiac iron overload are at increased risk of heart failure and are often treated by off-label combination therapy for a limited time to facilitate rapid removal of iron from the heart, allowing patients to move to a lower-risk status. This abstract describes off-label use of the combination of deferasirox and deferoxamine to treat patients with severe transfusional cardiac iron overload. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. Cappellini:Genzyme: Honoraria; Novartis: Honoraria, Speakers Bureau. Perrotta:Novartis: Research Funding. Karakas:Novartis: Honoraria, Research Funding. Viprakasit:GPO, Thailand: Honoraria, Research Funding; Shire: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Habr:Novartis: Employment. Wegener:Novartis: Employment. Shen:Novartis: Employment. Porter, MD on behalf of the HYPERION investigators:Shire: Consultancy, Honoraria; Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding.

Abstract Background Monoclonal immunoglobulins provide an indication of the tumor burden in patients with plasma cell neoplasms. Higher concentrations of serum free light chains in light chain predominant multiple myeloma have been shown to correlate with a poorer outcome. We examined the correlations of serum free light chain concentrations in light chain myelomas with survival, estimated glomerular filtration rate (eGFR) and other clinical and pathological parameters. Methods Records of patients with light chain multiple myelomas were reviewed. Highest concentration of serum free light chains for each patient were plotted to ascertain an inflection/change point. Survival, eGFR, and other clinical and pathological parameters were compared between the low and high light chain concentration groups. Results Plotting serum free light chain concentrations revealed an inflection point at a concentration of 455 mg/L apportioning patients in to 2 subgroups: 39 patients with low light chain concentrations and 26 patients with high concentrations. The high concentration group had more unfavorable pathology in bone marrow examination in terms of higher neoplastic plasma cell burden and high-risk cytogenetics. The survival rate and eGFR in the high concentration group were significantly worse than in the low concentration group. Conclusions As noted for light chain predominant multiple myeloma, high serum free light chain concentration in light chain multiple myelomas are associated with higher renal disease burden and shorter survival. Monitoring of serum free light chain concentrations and customizing treatments to address this parameter are warranted.

Unconventional energy sources have become increasingly important to the global energy mix. These include coal seam gas, shale gas and shale oil. The unconventional gas industry was pioneered in the United States and embraced following the first oil shock in 1973 (Rogers). As has been the case with many global resources (Hiscock), many of the same companies that worked in the USA carried their experience in this industry to early Australian explorations. Recently the USA has secured significant energy security with the development of unconventional energy deposits such as the Marcellus shale gas and the Bakken shale oil (Dobb; McGraw). But this has not come without environmental impact, including contamination to underground water supply (Osborn, Vengosh, Warner, Jackson) and potential greenhouse gas contributions (Howarth, Santoro, Ingraffea; McKenna). The environmental impact of unconventional gas extraction has raised serious public concern about the introduction and growth of the industry in Australia. In coal rich Australia coal seam gas is currently the major source of unconventional gas. Large gas deposits have been found in prime agricultural land along eastern Australia, such as the Liverpool Plains in New South Wales and the Darling Downs in Queensland. Competing land-uses and a series of environmental incidents from the coal seam gas industry have warranted major protest from a coalition of environmentalists and farmers (Berry; McLeish). Conflict between energy companies wanting development and environmentalists warning precaution is an easy script to cast for frontline media coverage. But historical perspectives are often missing in these contemporary debates. While coal mining and natural gas have often received “boosting” historical coverage (Diamond; Wilkinson), and although historical themes of “development” and “rushes” remain predominant when observing the span of the industry (AGA; Blainey), the history of unconventional gas, particularly the history of its environmental impact, has been little studied. Few people are aware, for example, that the first shale gas exploratory well was completed in late 2010 in the Cooper Basin in Central Australia (Molan) and is considered as a “new” frontier in Australian unconventional gas. Moreover many people are unaware that the first coal seam gas wells were completed in 1976 in Queensland. The first four wells offer an important moment for reflection in light of the industry’s recent move into Central Australia. By locating and analysing the first four coal seam gas wells, this essay identifies the roots of the unconventional gas industry in Australia and explores the early environmental impact of these wells. By analysing exploration reports that have been placed online by the Queensland Department of Natural Resources and Mines through the lens of environmental history, the dominant developmental narrative of this industry can also be scrutinised. These narratives often place more significance on economic and national benefits while displacing the environmental and social impacts of the industry (Connor, Higginbotham, Freeman, Albrecht; Duus; McEachern; Trigger). This essay therefore seeks to bring an environmental insight into early unconventional gas mining in Australia. As the author, I am concerned that nearly four decades on and it seems that no one has heeded the warning gleaned from these early wells and early exploration reports, as gas exploration in Australia continues under little scrutiny. Arrival The first four unconventional gas wells in Australia appear at the beginning of the industry world-wide (Schraufnagel, McBane, and Kuuskraa; McClanahan). The wells were explored by Houston Oils and Minerals—a company that entered the Australian mining scene by sharing a mining prospect with International Australian Energy Company (Wiltshire). The International Australian Energy Company was owned by Black Giant Oil Company in the US, which in turn was owned by International Royalty and Oil Company also based in the US. The Texan oilman Robert Kanton held a sixteen percent share in the latter. Kanton had an idea that the Mimosa Syncline in the south-eastern Bowen Basin was a gas trap waiting to be exploited. To test the theory he needed capital. Kanton presented the idea to Houston Oil and Minerals which had the financial backing to take the risk. Shotover No. 1 was drilled by Houston Oil and Minerals thirty miles south-east of the coal mining town of Blackwater. By late August 1975 it was drilled to 2,717 metres, discovered to have little gas, spudded, and, after a spend of $610,000, abandoned. The data from the Shotover well showed that the porosity of the rocks in the area was not a trap, and the Mimosa Syncline was therefore downgraded as a possible hydrocarbon location. There was, however, a small amount of gas found in the coal seams (Benbow 16). The well had passed through the huge coal seams of both the Bowen and Surat basins—important basins for the future of both the coal and gas industries. Mining Concepts In 1975, while Houston Oil and Minerals was drilling the Shotover well, US Steel and the US Bureau of Mines used hydraulic fracture, a technique already used in the petroleum industry, to drill vertical surface wells to drain gas from a coal seam (Methane Drainage Taskforce 102). They were able to remove gas from the coal seam before it was mined and sold enough to make a profit. With the well data from the Shotover well in Australia compiled, Houston returned to the US to research the possibility of harvesting methane in Australia. As the company saw it, methane drainage was “a novel exploitation concept” and the methane in the Bowen Basin was an “enormous hydrocarbon resource” (Wiltshire 7). The Shotover well passed through a section of the German Creek Coal measures and this became their next target. In September 1976 the Shotover well was re-opened and plugged at 1499 meters to become Australia’s first exploratory unconventional gas well. By the end of the month the rig was released and gas production tested. At one point an employee on the drilling operation observed a gas flame “the size of a 44 gal drum” (HOMA, “Shotover # 1” 9). But apart from the brief show, no gas flowed. And yet, Houston Oil and Minerals was not deterred, as they had already taken out other leases for further prospecting (Wiltshire 4). Only a week after the Shotover well had failed, Houston moved the methane search south-east to an area five miles north of the Moura township. Houston Oil and Minerals had researched the coal exploration seismic surveys of the area that were conducted in 1969, 1972, and 1973 to choose the location. Over the next two months in late 1976, two new wells—Kinma No.1 and Carra No.1—were drilled within a mile from each other and completed as gas wells. Houston Oil and Minerals also purchased the old oil exploration well Moura No. 1 from the Queensland Government and completed it as a suspended gas well. The company must have mined the Department of Mines archive to find Moura No.1, as the previous exploration report from 1969 noted methane given off from the coal seams (Sell). By December 1976 Houston Oil and Minerals had three gas wells in the vicinity of each other and by early 1977 testing had occurred. The results were disappointing with minimal gas flow at Kinma and Carra, but Moura showed a little more promise. Here, the drillers were able to convert their Fairbanks-Morse engine driving the pump from an engine run on LPG to one run on methane produced from the well (Porter, “Moura # 1”). Drink This? Although there was not much gas to find in the test production phase, there was a lot of water. The exploration reports produced by the company are incomplete (indeed no report was available for the Shotover well), but the information available shows that a large amount of water was extracted before gas started to flow (Porter, “Carra # 1”; Porter, “Moura # 1”; Porter, “Kinma # 1”). As Porter’s reports outline, prior to gas flowing, the water produced at Carra, Kinma and Moura totalled 37,600 litres, 11,900 and 2,900 respectively. It should be noted that the method used to test the amount of water was not continuous and these amounts were not the full amount of water produced; also, upon gas coming to the surface some of the wells continued to produce water. In short, before any gas flowed at the first unconventional gas wells in Australia at least 50,000 litres of water were taken from underground. Results show that the water was not ready to drink (Mathers, “Moura # 1”; Mathers, “Appendix 1”; HOMA, “Miscellaneous Pages” 21-24). The water had total dissolved solids (minerals) well over the average set by the authorities (WHO; Apps Laboratories; NHMRC; QDAFF). The well at Kinma recorded the highest levels, almost two and a half times the unacceptable standard. On average the water from the Moura well was of reasonable standard, possibly because some water was extracted from the well when it was originally sunk in 1969; but the water from Kinma and Carra was very poor quality, not good enough for crops, stock or to be let run into creeks. The biggest issue was the sodium concentration; all wells had very high salt levels. Kinma and Carra were four and two times the maximum standard respectively. In short, there was a substantial amount of poor quality water produced from drilling and testing the three wells. Fracking Australia Hydraulic fracturing is an artificial process that can encourage more gas to flow to the surface (McGraw; Fischetti; Senate). Prior to the testing phase at the Moura field, well data was sent to the Chemical Research and Development Department at Halliburton in Oklahoma, to examine the ability to fracture the coal and shale in the Australian wells. Halliburton was the founding father of hydraulic fracture. In Oklahoma on 17 March 1949, operating under an exclusive license from Standard Oil, this company conducted the first ever hydraulic fracture of an oil well (Montgomery and Smith). To come up with a program of hydraulic fracturing for the Australian field, Halliburton went back to the laboratory. They bonded together small slabs of coal and shale similar to Australian samples, drilled one-inch holes into the sample, then pressurised the holes and completed a “hydro-frac” in miniature. “These samples were difficult to prepare,” they wrote in their report to Houston Oil and Minerals (HOMA, “Miscellaneous Pages” 10). Their program for fracturing was informed by a field of science that had been evolving since the first hydraulic fracture but had rapidly progressed since the first oil shock. Halliburton’s laboratory test had confirmed that the model of Perkins and Kern developed for widths of hydraulic fracture—in an article that defined the field—should also apply to Australian coals (Perkins and Kern). By late January 1977 Halliburton had issued Houston Oil and Minerals with a program of hydraulic fracture to use on the central Queensland wells. On the final page of their report they warned: “There are many unknowns in a vertical fracture design procedure” (HOMA, “Miscellaneous Pages” 17). In July 1977, Moura No. 1 became the first coal seam gas well hydraulically fractured in Australia. The exploration report states: “During July 1977 the well was killed with 1% KCL solution and the tubing and packer were pulled from the well … and pumping commenced” (Porter 2-3). The use of the word “kill” is interesting—potassium chloride (KCl) is the third and final drug administered in the lethal injection of humans on death row in the USA. Potassium chloride was used to minimise the effect on parts of the coal seam that were water-sensitive and was the recommended solution prior to adding other chemicals (Montgomery and Smith 28); but a word such as “kill” also implies that the well and the larger environment were alive before fracking commenced (Giblett; Trigger). Pumping recommenced after the fracturing fluid was unloaded. Initially gas supply was very good. It increased from an average estimate of 7,000 cubic feet per day to 30,000, but this only lasted two days before coal and sand started flowing back up to the surface. In effect, the cleats were propped open but the coal did not close and hold onto them which meant coal particles and sand flowed back up the pipe with diminishing amounts of gas (Walters 12). Although there were some interesting results, the program was considered a failure. In April 1978, Houston Oil and Minerals finally abandoned the methane concept. Following the failure, they reflected on the possibilities for a coal seam gas industry given the gas prices in Queensland: “Methane drainage wells appear to offer no economic potential” (Wooldridge 2). At the wells they let the tubing drop into the hole, put a fifteen foot cement plug at the top of the hole, covered it with a steel plate and by their own description restored the area to its “original state” (Wiltshire 8). Houston Oil and Minerals now turned to “conventional targets” which included coal exploration (Wiltshire 7). A Thousand Memories The first four wells show some of the critical environmental issues that were present from the outset of the industry in Australia. The process of hydraulic fracture was not just a failure, but conducted on a science that had never been tested in Australia, was ponderous at best, and by Halliburton’s own admission had “many unknowns”. There was also the role of large multinationals providing “experience” (Briody; Hiscock) and conducting these tests while having limited knowledge of the Australian landscape. Before any gas came to the surface, a large amount of water was produced that was loaded with a mixture of salt and other heavy minerals. The source of water for both the mud drilling of Carra and Kinma, as well as the hydraulic fracture job on Moura, was extracted from Kianga Creek three miles from the site (HOMA, “Carra # 1” 5; HOMA, “Kinma # 1” 5; Porter, “Moura # 1”). No location was listed for the disposal of the water from the wells, including the hydraulic fracture liquid. Considering the poor quality of water, if the water was disposed on site or let drain into a creek, this would have had significant environmental impact. Nobody has yet answered the question of where all this water went. The environmental issues of water extraction, saline water and hydraulic fracture were present at the first four wells. At the first four wells environmental concern was not a priority. The complexity of inter-company relations, as witnessed at the Shotover well, shows there was little time. The re-use of old wells, such as the Moura well, also shows that economic priorities were more important. Even if environmental information was considered important at the time, no one would have had access to it because, as handwritten notes on some of the reports show, many of the reports were “confidential” (Sell). Even though coal mines commenced filing Environmental Impact Statements in the early 1970s, there is no such documentation for gas exploration conducted by Houston Oil and Minerals. A lack of broader awareness for the surrounding environment, from floral and faunal health to the impact on habitat quality, can be gleaned when reading across all the exploration reports. Nearly four decades on and we now have thousands of wells throughout the world. Yet, the challenges of unconventional gas still persist. The implications of the environmental history of the first four wells in Australia for contemporary unconventional gas exploration and development in this country and beyond are significant. Many environmental issues were present from the beginning of the coal seam gas industry in Australia. Owning up to this history would place policy makers and regulators in a position to strengthen current regulation. The industry continues to face the same challenges today as it did at the start of development—including water extraction, hydraulic fracturing and problems associated with drilling through underground aquifers. Looking more broadly at the unconventional gas industry, shale gas has appeared as the next target for energy resources in Australia. Reflecting on the first exploratory shale gas wells drilled in Central Australia, the chief executive of the company responsible for the shale gas wells noted their deliberate decision to locate their activities in semi-desert country away from “an area of prime agricultural land” and conflict with environmentalists (quoted in Molan). Moreover, the journalist Paul Cleary recently complained about the coal seam gas industry polluting Australia’s food-bowl but concluded that the “next frontier” should be in “remote” Central Australia with shale gas (Cleary 195). It appears that preference is to move the industry to the arid centre of Australia, to the ecologically and culturally unique Lake Eyre Basin region (Robin and Smith). 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