Journal articles on the topic 'Zinc Corporation'

The paper discusses organizing online ore monitoring on process conveyor belts at the operations of Kazakhmys Corporation LLC using EDXRF method implemented as an ore-controlling station (OCS) targeting ore size of -300 mm. OCS is supposed to achieve the objective of providing reliable silver detection measurements in the range of 1+ ppm. Objects of monitoring: copper-containing polymetallic ores delivered to Zhezkazgan, Balkhash and Karagaily processing plants for treatment (target elements include copper, zinc, lead, silver, cadmium, and iron) as well as ores transported by the main underground feeder belt at Nurkazgan Mine (copper, zinc, lead, silver, molybdenum, and iron). The ultimate of the studies was to produce an online report on quality and quantities of ore and metals delivered from each of ore suppliers; to adjust the tonnages dispatched by the various shafts and open pits in the online mode; obtain reliable proof for unbiased redistribution of metals back to the mining operations. Equipment used during the studies: EDXRF OCS RLP21T. Key features of the unit are also discussed. The results of bench-scale testing as well as industrial application of OCS RLP-21T are discussed leading to the conclusion of successful online monitoring of silver in ores sized from +1 ppm to -300 mm. The photographs were provided by S. A. Yefimenko.

The objective of this study was to evaluate the apical leakage of retrograde cavities filled with Portland Cement (Concrebrás S/A-MG-Brazil), ProRoot MTA TM (Dentsply International, Johnson City, TN, USA) and Sealapex (Kerr Corporation, Orange, California, USA) with addition of zinc oxide (Odahcam Herpo Produtos Dentários Ltda, Rio de Janeiro, RJ, Brazil). Forty-two extracted single-rooted human teeth were decoronated and used for this study. The root canals were instrumented at 1.0mm short of the apical foramen using the step-back technique to an apical ISO size 60. The roots were obturated with gutta-percha points and sealer Sealapex (Kerr Corporation-USA) and then 3mm of each root apex was sectioned at a 90° angle. Ultrasonic retrograde preparation was performed with a diamond tip to 3mm depth and the roots were randomly divided into 3 groups according to the filling material: G1-Portland, G2-ProRoot MTA, G3- Sealapex zinc oxide-added cement. The root surfaces were covered with nail varnish up to 2mm from the apical foramen, immersed in simulated tissue fluid for 30 days, and then immersed in 0.2% Rhodamine B solution for 24 hours for evaluation of marginal leakage. The results showed mean leakage of 0.75, 0.35 and 0.35 for groups 1, 2 and 3, respectively; however, Kruskal-Wallis test revealed that there was no statistically significant difference among the results (p>0.05).

Abstract Previously, we reported that supplementing a water soluble zinc via drinking water (0 to 80 mg/L) to nursery pigs improved ADG and G:F. To evaluate the efficacy of higher titrated levels of this water soluble zinc amino acid complex (ProPath®Zn LQ, Zinpro Corporation, Eden Prairie, MN) on growth performance, 280 crossbred pigs (5.5 kg BW; 19 d of age) were randomly allotted to four water treatments (7 pens/treatment; 10 pigs/pen). The water treatments were 0, 40, 80 and 160 mg Zn/L of water. Pigs were fed in 4 dietary phases with complex, nutrient-dense, corn-soybean meal-based diets: Phase 1 and 2 (2,500 and 1,750 mg Zn as ZnO/kg; d 1–7 and 7–14, respectively) and Phase 3 and 4 (200 mg Cu as CuSO4/kg; d 14–23 and 23–42, respectively). Pigs and feeders were weighed weekly to determine ADG, ADFI, and G:F. Water meters were used to record and calculate water disappearance and zinc intake. Data were analyzed as a randomized complete block design. Orthogonal polynomial contrasts were used to determine linear and curvilinear effects. Water and total zinc intake increased linearly (P < 0.001) with increasing water zinc concentration. From d 0–14 when high dietary zinc was fed, there were no differences (P > 0.10) in ADG, ADFI, or G:F. However, from d 14–42 when basal levels of zinc were fed, quadratic improvements in ADG (0.545, 0.561, 0.578, 0.546 kg; P < 0.05) and G:F (0.686, 0.706, 0.723, 0.702; P < 0.01) were observed with increasing zinc via water. Similarly for d 0–42, ADG (0.435, 0.440, 0.454; 0.434 kg; P = 0.07), G:F (0.726, 0.740, 0.763, 0.749; P = 0.05) and average ending wt (23.73, 23.97, 24.55, 23.70 kg; P = 0.07) improved quadratically with increasing zinc. In conclusion, supplementing ProPath®Zn LQ via water resulted in improvements in ADG and G:F for nursery pigs.

On 2 Feb. 1996, rooted cuttings of Pelargonium × hortorum L. H. Bailey cvs. Tango and Blues were planted in 750-cm3 (14 cm in diameter) pots containing peatmoss mixed with shredded tire rubber (2–6.0 mm particle size) at 0%, 20%, 40%, 60%, or 80%. Plants were irrigated by hand, drip, or ebb-and-fl ood, and were arranged in a split-plot experimental design. A wetting agent (Aqua Gro 2000 L, Aquatrols Corporation, Cherry Hill, N.J.) was mixed at the rate of 6 ml per 3750 ml of water and 120 ml of solution was applied to each plant. Greenhouse studies indicated that geraniums could be grown successfully in media containing up to 20% shredded tire rubber by volume when irrigated by hand. Plants grown in media containing more than 20% rubber were observed to be slow-growing and chlorotic. Tissue analysis of the plants indicated significantly increased levels of zinc in plants grown in media containing high percentages of rubber. Geraniums grown in media containing 80% rubber and irrigated using ebb-and-fl ood benches had the significantly highest levels of foliar zinc. Media porosity, percent air space, and bulk density increased, while water holding capacity decreased with increasing amounts of shredded tire rubber added to the media.

Abstract Background: Immunomodulatory drugs exhibit several anti-Multiple Myeloma (MM) activities including: growth arrest, antiangiogenesis, inhibition of tumor necrosis factor-alpha signaling and induction of apoptosis. The mechanism of action of the IMiD® compounds lenalidomide and pomalidomide that are responsible for these effects are starting to become clear. IMiD® compounds directly bind Cereblon (CBRN), a substrate receptor of the cullin ring E3 ligase (CRL4), and induce CRL4CRBN -mediated degradation of the zinc finger transcriptional repressors Aiolos and Ikaros by ubiquitin-mediated proteolysis. However, direct links between Aiolos or Ikaros degradation via the CRBN-Cul4 complex to the anti-MM activities of IMiD® drugs are poorly understood. Methods and Results: IMiD® compound-induced apoptosis in MM cells is associated with extended duration of treatment and increased caspase-8 activity, but the precise mechanism of caspase-8 activation and delayed onset of apoptotic effects in response to treatment are unknown. Here we show that both lenalidomide and pomalidomide induce caspase-8, but not capsase-9 activity, in multiple MM cell lines after 3 days of treatment and apoptosis after 4 days without inducing significant changes in total caspase-8, c-FLIP (a casapse-8 inhibitory molecule) or caspase-3 gene expression. Bioinformatic analysis of public datasets revealed that that the pro-apoptotic protein TRAIL may be induced by IMiD® compound treatment in a CRBN dependent manner. We confirmed in multiple cell lines that IMiD® compound treatment or knockdown of Aiolos or Ikaros induces TRAIL gene expression. Furthermore, IMiD® compound treatment in pomalidomide resistant cells that lack CRBN expression failed to induce TRAIL gene expression suggesting TRAIL induction is regulated through the established IMiD® drug mediated CRBN-Aiolos/Ikaros pathway. ChIP-PCR analysis confirmed that TRAIL is a direct transcriptional target gene of Aiolos and Ikaros in MM cells. Incubation of cells with a TRAIL neutralizing antibody was sufficient to partially attenuate IMiD® induced apoptosis, thus confirming the role of TRAIL in IMiD® drug induced MM cell apoptosis. Furthermore, TRAIL secretion into the media of IMiD® compound treated cells was significantly increased only after 2 days treatment explaining the delayed induction of apoptosis in treated cells. Interestingly, MM cell lines that are intrinsically resistant to the apoptotic effects of IMiD® compounds, despite degrading Aiolos and Ikaros in response to drug, displayed a decrease in TRAIL sensitivity. Conclusions: Taken together this data indicates that IMiD® drugs induce caspase-8 mediated apoptosis by directly inducing TRAIL gene expression via degradation of Aiolos and Ikaros. Additionally, this suggests that therapeutic interventions that can increase MM cell sensitivity to TRAIL might act synergistically with IMiD® compounds. Disclosures Amatangelo: Celgene Corporation: Employment, Equity Ownership. Bjorklund:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene: Employment, Equity Ownership. Klippel:Celgene Corporation: Employment, Equity Ownership. Daniel:Celgene Corporation: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership. Trotter:Celgene Corporation: Employment. Thakurta:Celgene Corporation: Employment, Equity Ownership.

Multiple myeloma is a malignancy of terminally differentiated plasma cells that are primarily resident in the bone marrow. Despite novel therapies, myeloma remains a fatal disease. Through interactions with immune cells in the bone marrow microenvironment, myeloma cells have been shown to facilitate their own proliferation and drug resistance. Therefore, targeting the immune support cells in the myeloma bone marrow microenvironment could add further value to existing treatment regimens. ZFP91, a C2H2-type zinc-finger protein, is a substrate of IMID drugs (An et al, Nat. Commun. 2017). The downstream target of ZFP91 in myeloma has been elusive so far. Our myeloma-specific ZFP91 interactome data and recent publications indicate an immune related function for ZFP91. A recent study also indicated that treatment of healthy volunteers with iberdomide, impaired the ability of monocytes to secrete IL-1β in response to LPS (Schafer PH, et al. Ann Rheum Dis 2018). To further investigate this, we generated CRISPR knockouts of IKZF1, IKZF3 and ZFP91, three major substrates of lenalidomide and iberdomide, in THP-1 monocytic cells. Upon LPS induction, loss of ZFP91 impaired the ability of THP-1 monocytic cells to secrete IL-1β (WT 70 pg/ml of IL-1β vs ZFP91-/- 4.5 pg/ml of IL-1β). Loss of IKZF1/3, the other two substrates of lenalidomide and iberdomide did not impair IL-1β secretion. IL-1β is a known activator of IL-6, a critical cytokine for myeloma cell proliferation. As a next step, we created a co-culture model to mimic a minimal myeloma tumor microenvironment with ANBL-6 (IL-6 dependent) myeloma cell line and primary bone marrow stromal cells in the presence of pre-conditioned media from LPS stimulated THP-1 monocytes. Preconditioned media from ZFP91-/- monocytes impaired proliferation of myeloma cells in the co-culture model due to lack of IL-1β, the inducer of IL-6 from the stromal cells. Mechanistically, loss of ZFP91 impairs the TLR4 signaling pathway. Thus, targeting ZFP91 impairs proliferation of myeloma cells within the bone marrow microenvironment by acting in trans from monocytes. Our findings for the first time identify a tumor cell proliferative role for ZFP91 in the myeloma tumor microenvironment. In addition, it establishes ZFP91 as an immune substrate of lenalidomide and iberdomide and could be a key player that mediates the immune functions observed. Disclosures Jeyaraju: Celgene Corporation: Employment, Equity Ownership. Kumari:Celgene Corporation: Employment. Amatangelo:Celgene Corporation: Employment, Equity Ownership. Bjorklund:Celgene Corporation: Employment, Equity Ownership. Hsu:Celgene Corporation: Employment. Thakurta:Celgene: Employment, Equity Ownership.

Abstract Previously, we reported that supplementing titrated levels of a water soluble zinc amino acid complex (ProPath®Zn LQ, Zinpro Corporation, Eden Prairie, MN) via water (0 to 80 mg/L) to nursery pigs resulted in a lower inflammatory response after LPS challenge. To evaluate the efficacy of higher titrated levels, 280 pigs (5.5 kg BW; 19-d old) were allotted randomly to water treatments: 0, 40, 80 and 160 mg Zn/L of water (7 pens/treatment; 10 pigs/pen). Pigs were fed corn-soybean meal based diets with added Zn as ZnO or Cu as CuSO4: Phase 1 (2,500 mg Zn/kg; d 1–7), Phase 2 (1,750 mg Zn/kg; d 7–14), Phase 3 (200 mg Cu/kg; d 14–23), and Phase 4 (200 mg Cu/kg; d 23–42). At d 23, pigs were challenged by i.m. injection of lipopolysaccharide (12 µg/kg BW). Blood, BW, and rectal temperature (RT) were obtained from two pigs per pen at h 0, 3, and 12 of the challenge. Increasing water zinc resulted in linear reductions in RT (P = 0.02) and serum TNF-α concentration (P = 0.05) at h 0 prior to LPS injection. Post-LPS injection, increasing water zinc decreased linearly RT at h 3 (P = 0.01) and serum Zn:Cu ratio at h 3 (P = 0.04) and 12 (P = 0.01), and decreased serum TNF-α concentration at all hours (quadratic, P &lt; 0.05). Additionally, increasing water zinc tended (linear, P = 0.07) to attenuate the decrease in BW following LPS from h 0–12. However, there were no effects on serum and salivary CRP concentrations (P &gt; 0.05) within 12 hours of LPS challenge. At d 42, salivary CRP concentration decreased (quadratic, P = 0.03) with increasing zinc. In conclusion, supplementing ProPath®Zn LQ via drinking water to nursery pigs mitigated the febrile response and decreased cytokine production during an acute immune challenge.

Background & Objectives:The study was conducted with objective to compare the horizontal condylar guidance (HCG) obtained by protrusive interocclusal records and panoramic radiographic images in completely edentulous patients.Materials & Methods:The horizontal condylar guidance was measured in 25 completely edentulous patients by protrusive interocclusal records using zinc oxide eugenol paste through a face bow transfer (HanauTM Spring bow, Whip Mix Corporation, USA) to a semi-adjustable articulator (HanauTM Wide-Vue Articulator, Whip Mix Corporation, USA). In the same patients, HCG was traced in the panoramic radiograph. The angles formed by the intersection of two lines: Frankfurt’s horizontal plane and posterior slope of articular eminence was measured using protractor to represent the horizontal condylar guidance angle on each side.Results:The mean difference between the horizontal condylar guidance angles values obtained using protrusive interocclusal record and panoramic radiograph was 2.68 degrees and 3.40 degrees for the right and the left side respectively, with the panoramic radiograph values being higher. This difference between the values was found to be highly significant between the two methods for the right side (t = 2.70, p = 0.012) and left side (t = 3.69, p = 0.001). A significant positive correlation was found between the horizontal condylar guidance obtained from protrusive interocclusal record and panoramic radiograph for the right (r = 0.643, p = 0.001) and left sides (r = 0.622, p = 0.001) separately.Conclusion:The panoramic radiographic tracing can be used to calculate the mean horizontal condylar guidance in the completely edentulous patients and these values can be used to programme semi-adjustable articulators avoiding the cumbersome process of obtaining protrusive interocclusal records.

The paper presents the results of studies of the influence of the Zn:Mg ratio on the hardenability, structure and complex of mechanical and corrosive characteristics of forgings with 150 mm thickness made of alloys based on Al–Zn–Mg–Cu system, manufactured in the production conditions of metallurgical plants of JSC AMR and Public Corporation “KUMZ”. It has been determined that an alloy of the Al–Zn–Mg–Cu system with Zn:Mg ratio of not less than 4,1:1 and copper mass content of not more than 1.2% has a higher hardenability compared to the 1933 alloy of standard composition, which ensures homogeneous structure and indicators of mechanical and corrosion properties over the thickness of semi-finished pro-ducts; in metallurgical industry at the stage of manufacturing this allows reducing the residual quenching stresses in massive forgings by means of straightening by reduction in an as-quenched state.

The geological industry of Kazakhstan is transiting to CRIRSCO, the international system of reporting standards for mineral reserves. In view of the set tasks, the problem of adjusting the geological and economic assessment of deposits is being updated in order to adapt it to the international requirements and to increase accessibility and transparency for a potential external investor. This research has been carried out on the basis of the Kazakhmys Corporation LLС, the largest international company engaged in exploring, mining and processing of various minerals. The authors of this paper have made an attempt to expand the geological and economic assessment of the enterprise by digitizing the key business processes. On the basis of the formed factual database of the geological and economic indicators and characteristics of the stratiform pyrite-copper-lead-zinc deposit Kusmuryn, which is part of the Kazakhmys Corporation LLС, the economic indicators of extracting associated components have been calculated. Digital transformation is a key area of technological development of the mining industry in Kazakhstan for the coming years. In this regard, automation of calculating the geological and economic assessment of the investigated field will allow the company not only to reduce investment and operating costs, but also to deepen the internal analytical work to monitor the effectiveness of the applied digital solutions. Transformation of the economy of Kazakhstan presupposes state support for promising regions. The article shows that transition of the Kusmuryn deposit to underground mining in the medium term will accelerate the solution of pressing regional problems and remove social tension in the monotowns adjacent to the deposit. In order to strengthen its position in the global economy, Kazakhstan strives to achieve socio-economic goals in the field of sustainable development. It has been established that changing the method of production and automation of business processes of the Kazakhmys Corporation LLС will have a positive effect on the energy efficiency due to more rational use of available technologies. The research will improve the validity of predictive management decisions to strengthen the financial and economic situation and the international positions of the mining and smelting enterprise.

Abstract The Izok Zn-Cu-Pb-Ag volcanogenic massive sulfide deposit is located 265 km south of Kugluktuk (Coppermine), Nunavut Territory, Canada, in the west-central Slave structural province. The Izok deposit is owned 100% by Inmet Mining Corporation and represents one of the largest undeveloped zinc-copper resources in North America. The Izok deposit is hosted within and near the top of a thick sequence of predominantly felsic pyroclastic rocks of late Archean age. The hanging-wall stratigraphy includes additional felsic volcaniclastic rocks, andesitic and basaltic flows, thin sulfide-rich iron formations, and turbiditic sedimentary rocks. The felsic volcanic rocks are intruded by intermediate dikes and sills, followed by gabbroic dikes and sills. Both intrusive suites are interpreted to be volcanic feeders to the overlying flows. All lithologies are subsequently cut by younger, irregular, granitic pegmatite and diabase dikes. The volcanic and sedimentary rocks are regionally metamorphosed to pyroxene hornfels grade. The massive sulfides occur within a large (kilometer-scale) Na-depleted sericitic alteration zone. The immediate footwall and hanging-wall rocks to the deposit are characterized by zones of muscovite-biotite-sillimanite, lesser chlorite-biotite-cordierite, and locally intense silicification and sodium metasomatism. All lithologies have been affected by younger Ca-metasomatism. As currently defined, the Izok deposit comprises a cluster of five complexly zoned composite lenses: the Northwest, North, Central West, Central East, and Inukshuk lenses. The first four lenses are amenable to open-pit mining, whereas the Inukshuk lens will require underground development. The total indicated mineral resource presently stands at 16.5 million tonnes with a grade of 2.2% Cu, 11.4% Zn, 1.1% Pb, and 60 g/t Ag. Inmet Mining Corporation is presently reviewing the economic feasibility of developing the property.

Background:The Global Leadership Initiative on Malnutrition (GLIM) criteria, the first international criteria for diagnosis of malnutrition, was released in 2018 [1]. Patients with rheumatoid arthritis (RA) are thought to be prone to malnutrition due to decreased food intake and increased muscle catabolism caused by chronic inflammation or pain. However, there has been no report to assess the nutritional status of RA patients in accordance with the GLIM criteria. In addition, commonly used blood nutrient indicators such as albumin might not be appropriate as nutritional indicators for RA because these values are affected by inflammation.Objectives:This study aims to examine the rates of malnutrition in RA patients according to GLIM criteria, and the relationship between blood nutrient indicators and the severity of malnutrition.Methods:In this study, we conducted a cross-sectional survey of 135 female RA patients in 2020. According to the GLIM criteria, patients were considered to be malnourished if patients had one of the following phenotypic: (1) low body mass index, (2) non-volitional weight loss, (3) reduced muscle mass, and one of the following etiologic: (1) reduced food intake or assimilation, (2) disease burden/inflammatory condition. Reduced muscle mass was evaluated by measuring calf circumference, and inflammatory condition was evaluated by Disease Activity Score (DAS) 28. In accordance with the GLIM criteria, the severity of malnutrition was judged as three levels: no problem, moderate, and severe malnutrition. Albumin, transthyretin, transferrin, retinol binding protein, zinc, iron, ceruloplasmin, and total cholesterol were assessed as blood nutrition indicators. Also grip strength was assessed. We compared each nutritional indicator among the three groups according to the severity of malnutrition using age-adjusted analysis of covariance, and examined the relationship between each nutritional indicator and the severity of malnutrition using receiver operating characteristic (ROC) analysis.Results:In RA patients, 20% were classified as severe malnutrition, and 40% were moderate or more. Serum iron levels were significantly lower in the severe malnutrition group compared to the no problem group (p = 0.001). In ROC analysis, serum iron, zinc, albumin, and grip strength (area under curve; AUC; 0.680, 0.696, 0.636, 0.790, respectively) were significant parameters for classification of moderate and severe malnutrition. Serum iron and grip strength (AUC for respective parameters were 0.741, 0.747) were significant parameters for classification of severe malnutrition.Conclusion:Evaluation based on the GLIM criteria showed that about 40% of RA patients were under moderate or severe malnutrition. It was suggested that serum iron and grip strength might be useful to predict the severity of malnutrition.References:[1]Cederholm T, Jensen GL, Correia MITD, Gonzalez MC, Fukushima R, Higashiguchi T, et al. GLIM criteria for the diagnosis of malnutrition – A consensus report from the global clinical nutrition community. Clinical Nutrition 2019; 38: 1-9.Acknowledgements:We thank to Tomoko Nakatsuka, and the Center for Drug & Food Clinical Evaluation, Osaka City University Hospital, for management and collection of the study data. We also thank to study participants.Disclosure of Interests:Yoshinari Matsumoto Grant/research support from: Yamada Research Grant, Yuko Sugioka: None declared, Masahiro Tada: None declared, Tadasi Okano Speakers bureau: AbbVie, Asahikasei, Astellas Pharma Inc, Ayumi Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiich Sankyo, Eisai, Janssen, Lilly, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Ono Pharmaceutical, Pfizer, Sanofi, Takeda Pharmaceutical, Teijin Pharma and UCB, Grant/research support from: AbbVie, Eisai, Mitsubishi Tanabe Pharma Corporation and Nipponkayaku, Kenji Mamoto: None declared, Kentaro Inui Speakers bureau: Daiichi Sankyo Co. Ltd., Mitsubishi Tanabe Pharma, Janssen Pharmaceutical K.K., Astellas Pharma Inc., Takeda Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Abbvie GK, Pfizer Inc., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd, Grant/research support from: anssen Pharmaceutical K.K., Astellas Pharma Inc., Sanofi K.K., Abbvie GK, Takeda Pharmaceutical Co. Ltd., QOL RD Co. Ltd., Mitsubishi Tanabe Pharma, Ono Pharmaceutical Co. Ltd., Eisai Co., Ltd., Daiki Habu: None declared, Tatsuya Koike Speakers bureau: AbbVie, Astellas Pharma Inc, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Janssen, Lilly, Mitsubishi Tanabe Pharma Corporation, MSD, Ono Pharmaceutical, Pfizer, Roche, Takeda Pharmaceutical, Teijin Pharma, and UCB, Grant/research support from: AbbVie, Astellas Pharma Inc, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Janssen, Lilly, Mitsubishi Tanabe Pharma Corporation, MSD, Ono Pharmaceutical, Pfizer, Roche, Takeda Pharmaceutical, Teijin Pharma, and UCB

Introduction.The correct diagnosis of neonatal sepsis is a relevant problem because sepsis is one of the most important causes of neonatal morbidity, mortality, and prolonged hospital stay. Calprotectin is an antimicrobial, calcium and zinc binding heterocomplex protein that could be used as a nonspecific marker for activation of granulocytes and mononuclear phagocytes. Calprotectin has been proposed for the diagnosis of inflammatory conditions. Our aim is to study serum calprotectin as a biomarker for neonatal sepsis diagnosis.Methods.41 (20 females, 21 males) infants who underwent blood culture due to suspected sepsis were enrolled in the study. Serum calprotectin was measured by a commercial ELISA assay (Calprest, Eurospital, Trieste, Italy). Statistical analysis was performed using the statistical software package Stata 13.1 (Stata Corporation, College Station, Texas, USA).Results.8 neonates (19.51%) showed sepsis with positive culture and 33 (80.49%) showed suspected sepsis. The optimal cut-off for calprotectin is 2.2 μg/mL with a sensitivity of 62.5% and a specificity of 69.7%.Conclusions.Calprotectin may be considered a promising early, sensitive, specific marker of sepsis thanks to the importance of calprotectin in defense mechanisms and physiological functions of the immune system.

Purpose – The purpose of this study was to investigate the performance of a single-bridge ZnO nanorod as a photodetector. Design/methodology/approach – The fabrication of the design sensor with ∼6-μm gap Schottky contacts and bridging of the ZnO nanorod were based on conventional photolithography and wet-etching technique. Prior to bridging, the ZnO nanorods were grown by the hydrothermal process. The 0.35 M seed solution was prepared by dissolving zinc acetate dihydrate in 2-methoxyethanol, and monoethanolamine, which acts as a stabilizer, was added drop-wise. Before starting the solution deposition, and oxide, titanium (Ti) and gold (Au) layer deposition, p-type (100) silicon substrate was cleaned with Radio Corporation of America (RCA1) and RCA2, followed by dipping in diluted hydrofluoric acid. The aged solution was dropped onto the surface of the Au microgap structure, using a spin coater at a spinning speed of 3,000 rpm for 45 seconds, and then dried at 300°C for 15 minutes, followed by annealing at 400°C for 1 hour. The hydrothermal growth was carried out in an aqueous solution of zinc nitrate hexahydrate (0.025 M) and hexamethyltetramine (0.025 M). Findings – In this study, ZnO nanorods were grown on a SiO2 substrate by the hydrothermal method. Microgap electrodes with ∼6-μm spacing were achieved by using the wet-etching process. After the growth process, an area-selective mask was utilized to reduce the number of rods between the nearby gap areas. The obtained single ZnO nanorod was tested for the UV-sensing application. The single ZnO nanorod photodetector exhibited a UV photoresponse, thereby indicating potential as a cost-effective UV detector. The response and recovery times of the fabricated device were 65 and 95 seconds, respectively. Structural analysis was captured using X-ray Diffraction (XRD), whereas surface morphology was determined using scanning electron microscopy. Originality/value – This paper demonstrates the effect of UV photon on a single-bridge ZnO nanorod between microgap electrodes.

Abstract A 42-d research study evaluated effects of feeding beef steers increasing levels of dietary Zn from Zn methionine (AAC-Zn; ZINPRO, Zinpro Corporation, Eden Prairie, MN) with or without supplemental Cu from Cu amino acid complex (AAC-Cu; Availa Cu, Zinpro Corp.) concurrently with ractopamine hydrochloride (RAC; Optaflexx, Elanco Animal Health, Greenfield, IN). One hundred-twenty steers (mean BW = 624 kg), ≤ 50 d from projected harvest were randomized to three pens (40 steers/pen) equipped with GrowSafe Systems (Calgary AB, Canada) feed bunk technology. Each pen was assigned to one of three treatment diets: 1) basal finishing diet + 30 mg Zn/kg DM from AAC-Zn (CON); 2) basal finishing diet + 90 mg Zn/kg DM from AAC-Zn (AAC-Zn90); or 3) AAC-Zn90 diet + 10 mg Cu/kg DM from AAC-Cu (AAC-Zn/Cu). Following allocation to treatments, cattle were acclimated to pen cohorts and GrowSafe feed bunks for 7 days. All steers were fed 300 mg RAC∙hd-1∙d-1 starting 35 d prior to harvest. Individual feed intake measurements began with RAC feeding and continued for 35 d until cattle were shipped for harvest. Carcass data were collected from each steer. Data were analyzed with individual animal as the experimental unit using PROC MIXED and PROC GLIMMIX procedures of SAS 9.4 (SAS Institute, Cary, NC). Numerically AAC-Zn90 fed cattle had heavier carcass weights than CON and AAC-Zn/Cu. Steers fed AAC-Zn90 had greater (P = 0.02) marbling scores compared to AAC-Zn/Cu. Steers fed AAC-Zn90 had lower backfat thickness (P = 0.02) and numerically greater marbling scores compared to CON. A biphasic program of feeding a lower level of AAC-Zn for the duration of the finishing phase followed by an increased rate of AAC-Zn during RAC feeding may optimize overall live and carcass response and improve total individual animal value.

Clinical Relevance High-viscosity glass-ionomer cements (HVGICs) used with atraumatic restorative treatment can be repaired with light- or self-cured adhesive systems; however, the repair bond strength of two-step, self-etching and one-step adhesives in the light-cure mode surpass one-step self-cure adhesives. Working on a feasible self-cure approach in the absence of such in rural areas as well as in war zones is of prime importance. SUMMARY Objectives: Despite the success rate of high-viscosity glass-ionomer cements (HVGICs) used in atraumatic restorative treatment (ART) restorations, partial or bulk fracture of the proximal portion has been recorded to be one of the main causes of proximal restoration failures. Repair of these restorative materials requires a practical solution, especially in cases where there is a lack of electricity. Thus, the purpose of this study was to evaluate the repair microshear bond strength (μSBS) of three HVGICs using a resin composite in association with adhesive systems having different curing modes (ie, light- vs self-curing mode). Methods and Materials: A total of 105 discs (12 mm in diameter and 2 mm thick) of three HVGICs: GC Fuji IX GP Fast (GC Corporation, Tokyo, Japan); Fuji IX GP glass-ionomer cement containing chlorhexidine (GC Corporation, Tokyo, Japan); and ChemFil Rock zinc-reinforced HVGIC (Dentsply De-Trey GmbH, Konstanz, Germany) were prepared. Each specimen was divided into three horizontal sections, according to the tested adhesive system or curing mode: Clearfil SE Bond 2 (two-step, self-etch adhesive); (Kuraray Noritake Dental Inc., Tokyo, Japan) in light-cure mode; Clearfil Universal Bond (one-step, self-etch adhesive); (Kuraray Noritake Dental Inc., Tokyo, Japan) in light-cure mode; or Clearfil Universal Bond (one-step, self-etch adhesive); (Kuraray Noritake Dental Inc., Tokyo, Japan) in self-cure mode, mixing it with Clearfil DC Activator (Kuraray Noritake Dental Inc., Tokyo, Japan). A resin composite microcylinder was bonded to each horizontal section of each specimen using starch tubes. The bonded discs were stored in artificial saliva at 37°C for 24 hours. A μSBS test was conducted using a universal testing machine, while failure modes were determined using scanning electron microscopy. Data were statistically analyzed using two-way analysis of variance (ANOVA), one-way ANOVA, and Bonferroni post hoc tests (α=0.05). Results: Two-way ANOVA revealed a statistically significant effect for the adhesive systems (p&lt;0.01) and not for the HVGICs (p=0.05) nor their interactions (p=0.99). When using Clearfil SE Bond 2 and Clearfil Universal in a light-cure mode, significantly higher μSBS values were found when compared with Clearfil Universal in a self-cure mode. Conclusions: The three tested HVGICs can be successfully repaired using two-step or one-step self-etch adhesive systems. The one-step self-etch adhesive system in light-cure mode is preferred when compared with the self-cure mode.

Transcriptional regulators (TFs) involved in cell-growth, differentiation and survival of AML stem/progenitor cells (LSCs) include RUNX1, PU.1, CEBPα, c-Myb and c-Myc. LSD1 (KDM1A) is an FAD-dependent amine-oxidase that demethylates mono and dimethyl histone H3 lysine 4 (H3K4Me1 and H3K4Me2). LSD1 is part of the repressor complexes involving GFI1, CoREST and HDAC1/2, that regulate active super-enhancers/enhancers (SEs/Es) and their target genes, mediating transcriptional repression and differentiation block in LSCs. GFI1 is a zinc-finger transcriptional repressor involved in AML development and differentiation. GFI1 contains an N-terminal domain through which it binds to the CoREST/LSD1/HDAC1/2 complex to regulate differentiation in LSCs. CRISPR-suppressor scanning revealed that enzymatic activity of LSD1 was not required for LSC differentiation, instead disruption of binding of LSD1 to GFI1 and CoREST induced differentiation in LSCs. LSD1 and GFI1 expression correlates with worse prognosis in MDS/AML. In present studies, we demonstrate first-time ever that knockout (KO) or degradation of LSD1 utilizing CRISPR-Cas9 or LSD1-FKBP12(F36V) and dTAG-13, respectively, disrupted LSD1-binding to GFI1/1B and CoREST, inhibiting colony growth and inducing differentiation markers (CD86 and CD11b) and morphologic differentiation of AML and post-MPN sAML blast progenitor cells (BPCs). CRISPR-mediated knockout of LSD1 in the AML OCI-AML5 and sAML SET2 cells significantly increased the permissive H3K4Me2/3-marked chromatin, reduced H3K27Ac occupancy at SEs/Es (by ChIP-Seq), especially of c-Myc and CDK6, as well as repressed DNMT1, CoREST, c-Myc, CDK6, and c-KIT, while inducing GFI1, PU.1, CEBPα, p21, CD11b, and CD86 levels (log2 -fold change by RNA-Seq and by Western analyses). This correlated with growth inhibition, % differentiation and apoptosis of AML and sAML cells. CRISPR-mediated GFI1-KO ± the irreversible LSD1 inhibitor (LSD1i) (INCB059872, INCB), repressed GFI1 levels, yet enhanced expressions of PU.1, p21 and CD11b and significantly increased % morphologic differentiation. Treatment with INCB (0.25 to 1.0 µM) also disrupted binding of LSD1 to GFI1 and to CoREST, increased GFI1/1B and PU.1 and repressed c-Myc protein levels, while significantly inhibiting colony growth, inducing differentiation and loss of viability of AML and post-MPN sAML (SET2 and HEL92.1.7) cells, as well as patient-derived AML and post-MPN sAML blasts (p &lt; 0.01). Following INCB treatment, ATAC-Seq analysis demonstrated gained peaks in GFI1 and PU.1-target genes. Following H3K27Ac ChIP-seq analysis rank-ordering of SEs (ROSE) plot highlighted active SEs of RUNX1, GFI1, BCL2, PU.1, IRF8 and SMYD3, accompanied by increased H3K27Ac occupancy at the chromatin of GFI1 and PU.1 targets. Notably, INCB treatment also increased BRD4 occupancy, especially at the GFI1 and PU.1-target genes. RNA-Seq analysis showed that INCB treatment perturbed mRNA expressions, with positive normalized enrichment scores (NES) for interferon α, inflammatory-response, GFI1-targets and E2F-target gene-sets, and negative NES for c-Myc-targets and oxidative-phosphorylation gene-sets. RNA-Seq analyses of INCB-treated compared to untreated OCI-AML5 and SET-2 cells also demonstrated log2 fold-increase in the mRNA expressions of GFI1, PU.1 and CEBPα target-genes. Utilizing a protein domain-scanning CRISPR-Cas9 sgRNA screen followed by LSD1i treatment, present studies also demonstrate co-dependencies, including BRD4, in AML cells. BET inhibitor (BETi) treatment also depleted LSD1 protein levels, and co-treatment with the BETi OTX015 and INCB induced synergistic lethality in AML and post-MPN sAML blasts (Combination Indices &lt; 1.0). Pre-treatment with INCB re-sensitized JAKi-resistant sAML cells to ruxolitinib-induced apoptosis and BETi-resistant post-MPN sAML cells to BETi-induced apoptosis. Notably, co-treatment with INCB (1.5 mg/kg) and ruxolitinib (20 mg/kg) or OTX015 (50 mg/kg), administered orally for 21 days, compared to ruxolitinib alone or vehicle control, significantly reduced the sAML burden and improved survival of immune-depleted mice engrafted with luciferized sAML HEL92.1.7 xenografts (p &lt; 0.01). Collectively, these findings support further pre-clinical development of LSD1i-based combinations with ruxolitinib and BETi against post-MPN sAML. Disclosures Bose: CTI BioPharma: Honoraria, Research Funding; NS Pharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kartos Therapeutics: Honoraria, Research Funding. Kadia:Incyte: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Genentech: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Honoraria; Ascentage: Research Funding; Astellas: Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Astra Zeneca: Research Funding; BMS: Honoraria, Research Funding. Verstovsek:CTI Biopharma Corp: Research Funding; AstraZeneca: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; ItalPharma: Research Funding.

Abstract Introduction Dental readiness, one critical component of medical readiness, is adversely impacted by dental emergencies. Many dental emergencies require restorative materials such as glass ionomers, resins, and zinc oxide eugenols to remedy them. The Authorized Dental Allowance List (ADAL) and Authorized Medical Allowance List (AMAL) contain the equipment and materials used by Navy dentists to treat Sailors and Marines. These supplies are subjected to harsh storage conditions on deployments. Much is known about how materials behave when stored at room temperature, but less is known about how their properties are affected after exposure to high temperatures and humidity. We subjected five dental restorative materials to storage in aggravated conditions, and then tested them to determine which products are more robust. Materials and Methods Unopened packages of Fuji Triage, Fuji IX GP (both GC America Inc., Alsip, Illinois), TPH Spectra ST Low Viscosity, Intermediate Restorative Material (both Dentsply Sirona, York, Pennsylvania), and Herculite XRV (Kerr Corporation, Orange, California) were exposed to 0, 5, or 10 days’ storage at 30–60°C with 95% relative humidity. After storage in these aggravated conditions, we tested the compressive strength, hardness, elastic modulus, flexural strength, flexural modulus, sorption, and solubility of each material. Results The physical properties of all materials were affected by storage in aggravated conditions, though the properties of some materials degraded more than others. Both glass ionomers, Fuji Triage (P = 0.0012) and Fuji IX GP (P = 0.0031), and the composite Herculite XRV (P = 0.0253) lost compressive strength after 5 or 10 days in aggravated conditions. The hardness values for all materials were affected (P &lt; 0.05) by the aggravated conditions, though the elastic modulus of TPH Spectra was not affected (P &gt; 0.05). None of the materials lost flexural strength (P &gt; 0.05) or had changes in their flexural modulus (P &gt; 0.05). The water sorption behavior of Fuji Triage (P = 0.0426) and Fuji IX GP (P = 0.0201) changed after 10 days of aggravated storage, and the solubility of all materials was altered by the harsh conditions. Conclusion Some materials degrade more than others in aggravated conditions. Both resin composite materials were more resistant to high temperatures and humidity levels than the glass ionomers tested. These changes in physical characteristics should be considered when reviewing or optimizing the ADAL/AMAL for different projected operational environments.

Abstract Abstract 1983 The myeloproliferative neoplasms (MPNs), PV, ET and IMF, harbor a common gain-of-function mutation of JAK2V617F but in the past several years other molecular lesions have been noted as well such as mutation of TET2, chromsomal gains and losses, aberrant mRNA expression and aberrant microRNA expression. Since miRNAs are important regulators of hematopoiesis, we measured miRNA expression levels in CD34+ cells isolated from 8 patient samples (4 PV with JAK2V617F, 3 ET with wild-type JAK2 and 1 IMF with unknown JAK2 status) and 4 healthy controls using a Taqman Low Density Array (TLDA) representing 667 known miRNAs. We identified 28 miRNAs that were significantly deregulated in MPN patients compared to controls (p<0.05). Many of these miRNAs (18/24; 75%) were also deregulated in an independent miRNA array study using MPN patient granulocytes (n=39, 25 PV, 14 ET). Among these miRNAs, miR-9 expression was significantly upregulated in MPN patient CD34+ cells as well as in mature granulocytes. Furthermore, miR-9 expression was responsive to modulation of JAK2 activity in both gain of function (overexpression of JAK2V617F in TF-1 cells) and loss of function (inhibition of JAK2 activity in HEL cells) systems, suggesting that miR-9 may be dysregulated by aberrant JAK2V617F signaling. Analysis of miR-9 expression in ex-vivo, uni-lineage human CD34+ cultures, revealed that miR-9 is expressed at low levels during erythropoiesis, while levels gradually increase during myeloid differentiation. To determine how deregulated expression of miR-9 affected erythropoiesis, we transduced human bone marrow CD34+ cells (AllCells) with empty vector or miR-9 lentivirus, and examined erythroid differentiation and proliferation in liquid culture over 12 days. miR-9 expressing cells displayed a consistent growth advantage (∼30%), and accelerated erythroid differentiation (CD71+, GlyA+) at days 7 and 9. HITS-CLIP is a high throughput miRNA target prediction method developed in the Darnell lab based on crosslinking Argonaute protein to miRNA and target mRNA, providing highly specific identification of direct miRNA targets. We previously identified genes differentially expressed in PV patient CD34+ cells compared to normal CD34+ cells using Affymetrix HG-U133A arrays (117 genes, p<0.05). A comparison of predicted miR-9 mRNA targets identified using HITS-CLIP in P13 mouse brain, with genes downregulated in PV patient microarray studies, identified KLF4 which encodes a zinc finger protein involved in pluripotency and YWHAZ a 14-3-3 protein involved in signaling pathways regulating proliferation and survival as potential miR-9 targets relevant to aberrant hematopoiesis in MPN. Dysregulated cell growth in MPN may result in part from aberrant miRNA expression. Disclosures: Carroll: Sanofi Aventis Corporation: Research Funding; Kyowa Hakko Kirin Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Research Funding.

Pigs are useful models for studying human diseases because of the similarity of their anatomy and physiology. Recent advances in genome editing techniques such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat-associated Cas9 system (CRISPR/Cas9) have made it possible to produce animals for specific purposes. Especially, recent application of the CRISPR/Cas9 system improved the efficiency of genome editing in pigs with higher targeting efficiency or percentage of desired mutation compared to other meganucleases (ZFNs and TALENs). The klotho deficiency in small animals such as mice is characterised by an extremely shortened life span with multiple aging-like phenotypes similar to human premature-aging syndromes. However, limited information is available on the function of klotho in large animals such as pigs. The objective of this study was to determine whether the use of non-selected porcine fibroblasts electroporated with Cas9/sgRNA ribonucleoproteins, targeting the klotho gene, for somatic cell nuclear transfer (SCNT) results in high mutation rates in embryos. A CRISPR sgRNA specific for the klotho gene was designed and sgRNA (targeting exon 3 of klotho) and type 2 Cas9 RNPs (total 36 μg, 1:4 ratio, respectively) were transfected into porcine fibroblasts via Neon (Life Technologies) with a single DC pulse of 1400 V for 30 ms. Then, transfected fibroblasts were cultured for 1 day and used randomly for SCNT without selection. SCNT was performed by enucleation of in vitro-matured porcine oocyte, followed by injection of non-selected donor cells, fusion with a single DC pulse of 200 V/mm for 30 μs using an electro cell fusion generator (LF101; Nepa Gene Co.), and electrical activation with a single DC pulse of 150 V/mm for 60 μs using a BTX Electro-Cell Manipulator 2001 (BTX Inc.). The SCNT embryos were cultured in PZM5 culture medium to Day 7 and analysed for the presence of modifications to the klotho gene. Blastocysts were classified as modified if they contained an INDEL as measured by both T7E1 assay and deep sequencing of PCR amplicons spanning the targeted exon. The klotho modification rate was 65% (n = 13), of which 38.5% (n = 5) of the embryos contained biallelic modifications. In conclusion, SCNT with non-selected donor cells transfected with Cas9/sgRNA RNPs might be an efficient and simple tool to produce klotho deficient pigs as models for human diseases. Further studies are required to generate klotho deficient pigs by performing embryo transfer to the recipients. This study was supported by Korea Institute of Planning and Evaluation for Technology in food, agriculture, forestry and fisheries (#311011–05–5-SB010, #114059–03–2-SB010), Research Institute for Veterinary Science, TS Corporation and the BK21 plus program.

Abstract Numerous cellular effects have been attributed to IMiDs lenalidomide (LEN) and pomalidomide (POM) over the years. However, the zinc finger transcription factors Aiolos (IKZF3) and Ikaros (IKZF1) were identified only recently as substrates targeted for destruction in the presence of IMiDs compounds. LEN and POM bind directly to cereblon (CRBN), a substrate receptor of the cullin ring E3 ligase 4 (CRL4). Binding of these compounds to CRBN triggers the activation of CRL4CRBN, ubiquitylation and destruction of Aiolos and Ikaros. We systematically compared growth, gene expression, and signal transduction responses elicited by doxycycline-inducible, stable Aiolos knockdown or POM treatment in MM cell lines, and their POM-resistant counterparts. Upon exposure to POM, U266 MM cells undergo rapid degradation of Aiolos and Ikaros (90 min) and subsequent downregulation of IRF4 and Myc at 72 hr. At 72-96 hr, a decrease in proliferation and an increase in apoptosis are also observed. U266 MM cells selected in vitro for resistance to POM have lost CRBN expression and consequently no longer downregulate Aiolos and Ikaros after POM administration. Knockdown of Aiolos in these POM-resistant U266 MM cells is sufficient to inhibit their proliferative capacity by 50%, while Aiolos knockdown in POM-sensitive cells caused a greater inhibition of proliferation (90%). This suggests that MM cells with acquired resistance are still dependent on Aiolos for growth, but that a second mechanism may contribute to the antitumorigenic effect of Aiolos downregulation in POM-sensitive U266 cells. We have found that treatment with LEN or POM induces expression of antiviral response genes in MM cells. The induction of interferon (IFN)-stimulated genes (ISGs) such as DDX58, IFIT1, IFIT3, XAF1, ISG15, IFI44, and IFI27 are seen by qPCR in 8 hr of compound treatment (1.8- to 5-fold increase in transcript level) and this effect is further enhanced at 24 and 72 hr. Of note, this response is not accompanied by an increase in β IFN production. The IMiD compound-induced upregulation of the antiviral response correlates with CRL4-CRBN-mediated destruction of the lymphoid restricted transcription factor, Aiolos. In agreement with this, Aiolos knockdown by shRNA is sufficient to trigger a similar effect. These data suggest that Aiolos functions as a transcriptional repressor of ISGs, regulating the antiviral response. Consequently, Aiolos chromatin immunoprecipitation and sequencing (ChIP-Seq) experiments were performed, demonstrating that Aiolos binds near the transcription start site of numerous ISGs, including DDX58, IFIT1, ISG15, XAF1, IFI44, and IFI35. In addition, our data suggest that Aiolos co-binds with STAT and IRF family transcription factors and thereby co-regulates expression of these genes. STAT1 is part of the ISGF3 complex that drives ISG transcription upon viral infection. POM-resistant MM cells lacking CRBN expression do not have STAT1 activity and do not upregulate ISGs upon Aiolos knockdown, even though Myc and IRF4 are still being downregulated. In order to elucidate the relevance of the ISG expression in patients receiving IMiD treatment, we compared the gene expression profile of 12 patients after relapse or disease progression. Paired pre- and posttreatment samples from bone marrow-isolated CD-138 cells were evaluated with RNAseq and gene set enrichment analysis. We found an overall decrease in expression of ISGs, with significant negative enrichment of genes involved in IFN α, β, and γ signaling in relapsed patients. These data from clinical samples confirmed the importance and relevance of the ISGs in the response to IMiDs. In conclusion, our results indicate that Aiolos is a substrate of consequence in IMiD-sensitive MM cells, based on at least 2 pathways: driving the Myc-IRF4 feedback loop and repressing the antiviral pathway. Both in vitro and in vivo patient data suggest that one mechanism of IMiD resistance may be the abrogation of the STAT1 pathway resulting in subsequent blunting of the ISG induction. Finally, while upregulation of ISGs by IMiD treatment may serve as a relevant diagnostic marker of patient responsiveness to these drugs, these data highlight how response and resistance of the IMiD drugs are regulated by the interplay between complex pathway networks, suggesting that the measurement of only one component will not necessarily define the clinical course and outcomes for an individual patient. Disclosures Havens: Celgene Corporation: Employment, Equity Ownership. Bjorklund:Celgene Corp: Employment, Equity Ownership. Kang:Celgene Corp: Employment, Equity Ownership. Ortiz:Celgene Corp: Employment, Equity Ownership. Fontanillo:Celgene Corp: Employment, Equity Ownership. Amatangelo:Celgene Corporation: Employment, Equity Ownership. Lu:Celgene Corp: Employment. Lopez-Girona:Celgene Corp: Employment, Equity Ownership. Bahlis:Celgene Corp: Honoraria, Research Funding. Thakurta:Celgene Corp: Employment, Equity Ownership. Trotter:Celgene Corp: Employment, Equity Ownership. Gandhi:Celgene Corp: Employment, Equity Ownership. Klippel:Celgene Corp: Employment. Chopra:Celgene Corp: Employment, Equity Ownership.

Abstract The bromodomain and extraterminal (BET) proteins recognize acetylated lysine residues on histone tails and recruit transcriptional machinery to promote gene expression. The BET proteins are attractive drug targets because they regulate the expression of MYC, BCL2 and NF- κB target genes. We investigated the therapeutic potential of CPI-0610, an inhibitor of BET proteins, currently in Phase I testing in multiple myeloma (MM). Our preliminary data show that human MM cell lines are sensitive to BET inhibition, with IC50 values of 800-1000 nM being observed in MM.1S, MM.1R, RPMI-8226, LR5, H929 and U266 cell lines in 72h culture. We further show that CPI-0610 inhibits MM cell growth in the presence of cytokines and when co-cultured with bone marrow stromal cells. CPI-0610 induces apoptosis and G1 cell cycle arrest associated with MYC downregulation. However, protein levels of BCL2, NF- κ B and MCL1 remain unchanged in MM cells upon BET inhibition. The zinc finger transcriptional factor Ikaros (IKZF1) is highly expressed in MM (GEO dataset GSE36133). It is actively transcribed in the MM.1S cell line with an active transcription start site occupied by BRD4 and MED1 (Loven J et al. Cell 2013). Interestingly, we found that CPI-0610 suppresses Ikaros and IRF4 expression at the levels of both transcription and protein in MM cells. With the use of doxycycline-inducible shRNAs targeting IKZF1, IRF4 and MYC, we identified a positive feedback mechanism that is critical for MM cell survival. Individual knockdown of IRF4, IKZF1 or MYC all lead to induction of apoptosis in MM cells. Suppression of IRF4 decreases both Ikaros and MYC protein expression, suggesting that IRF4 is upstream of both Ikaros and MYC. Downregulation of MYC protein expression is observed following IKZF1 knockdown, suggesting that MYC is downstream of Ikaros. Finally, we observed a decrease in IRF4 protein level upon MYC downregulation, implicating a feedback mechanism from MYC to IRF4. Together, these data illustrate a molecular sequence of events going from IRF4 to IKZF1 to MYC and then back to IRF4, forming a positive feedback loop in MM cells. Based on the observation that shRNA-mediated knockdown of MYC and IKZF1 are toxic to MM, we combined CPI-0610 with lenalidomide, an immunomodulatory drug which stabilizes cereblon and facilitates Ikaros degradation in MM cells (Kronke J et al., and Lu G et al., Science 2014). We observed a synergistic cytotoxic effect in the cell lines tested (MM.1S and RPMI-8226). The enhanced cytotoxic effect of the combined treatment in MM cell lines is due in part to suppression of MYC, IKZF1 and IRF4. Ongoing studies will focus on understanding the molecular mechanism underlying this synergistic combination and validating its efficacy in vivo in order to provide a rationale for clinical protocols of BET inhibitors in MM. Disclosures Mertz: Constellation Pharmaceuticals: Employment, Equity Ownership. Sims:Constellation Pharmaceuticals: Employment, Equity Ownership. Cooper:Constellation Pharmaceuticals: Employment, Equity Ownership. Raje:Celgene Corporation: Consultancy; Eli Lilly: Research Funding; Takeda: Consultancy; Amgen: Consultancy; Onyx: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy; BMS: Consultancy; Acetylon: Research Funding; Millenium: Consultancy.

In the conditions of the field experiments conducted during the 2015–2016 vegetation seasons retardants Medax Top, 1.0 l/ha (prohexadione-Са and mepiquat-chloride), appeared more effective than Terpal, 1.5 l/ha (mepiquat-chloride and ethephon), on field plots with high-yield varieties. Foliar application of Megafol promoted the productivity of winter wheat varieties Smuglyanka and Podolyanka and reduced the negative influence of retardants on the wheat plants in the vegetation seasons which were characterized by moisture deficit. The influence of modern retardants – prohexadione-Ca + mepiquat-chloride (Medax Top) and mepiquat-chloride + etefone (Terpal, both BASF, Germany) on the accumulation of some macro- and micronutrients in winter wheat plants was determined. The assays were performed on an ICP-MS Agilent 7700x mass spectrometer (Agilent Technologies, USA) with ICP-MS Mass Hunter WorkStation. Samples of winter wheat plants were taken in the phase of flowering and grain ripening. The samples were dried, homogenized, 0.400 gof weight was dissolved in ICP-grade nitric acid in the Milestone Start D (Milestone Inc., USA). All solutions were prepared on 1st class water (18 MΩ cm–1) obtained on the Scholar-UV Nex Up 1000 (Human Corporation, Korea) water purification system. The ICP-MS Complete Standard IV-ICPMS-71A was used as the external standard, and the internal standard was Sc, both of Inorganic Ventures, USA. According to the ICP-MS results of plant samples of winter wheat of Smuglylanka and Podolanka, it has been shown that, in conditions of wheat growing on light soils of Polissya, modern compositional retardants affect the ionome of plants during vegetation, as well as change the content of inorganic elements in the grain. It was found that winter wheat of middle-stem Podolyanka type, of the intensive type, reacted more responsively to retardant treatment than the short-stem-type highly intensive Smuglyanka type. At the same time, there was an increase in the content of nutrients in winter wheat of the Podolyanka variety. It should be noted that wheat grain of the Smuglyanka variety contained a significantly higher pool of macro- and trace elements than the Podolyanka variety. It was established that the treatment of winter wheat Podolyanka varieties by mepiquat-chloride and ethephon (Terpal, 1.5 l/ha) positively influenced the accumulation of potassium, magnesium and calcium and manganese, copper and zinc in the grain. We found that foliar application of compositions of amino acids simultaneously with retardants can reduce the negative action of PGR’s on formation of the harvest in conditions of drought and influence the maintenance of composition of inorganic elements in the plants and in the grain. The composition of retardants with the content of cyclohexadione derivative (Medax Top) also significantly influenced the changes in the content of inorganic elements in plants and grains. We note the significant increase in the content of magnesium in the leaves and in grain due to the action of Medax Top. These differences in reaction of winter wheat varieties to the action of retardants of the class of cyclohexadione are important for clarifying the systems of nutrition of crops in intensive growing technologies, especially in the conditions of drought and high temperatures. Reduction in the pools of a number of inorganic elements in plants, for example iron, by the action of retardants may be due to the constraints on the entry of these elements from the poor soils of the Polissya zone and should be compensated via foliar nutrition. Also, the peculiarities of the activity of plant growth regulators have been shown to indicate a close relationship between signal systems of plants and changes in ionome.

Purpose – The following paper is a “Q & A interview” conducted by Joanne Pransky of Industrial Robot Journal as a method to impart the combined technological, business and personal experience of a prominent, robotic industry engineer-turned successful business leader, regarding the commercialization and challenges of bringing technological inventions to market while overseeing a company. This paper aims to discuss these issues. Design/methodology/approach – The interviewee is Aldo Zini, President and CEO of Aethon, Inc., a robotics and software company that has developed an innovative automated platform to improve internal supply logistics. In this interview, Zini shares some of the technical and business details that have led up to the latest version of Aethon’s core product, the TUG, a mobile autonomous robot with more than 450 installs worldwide. Findings – Zini received a BS in Industrial Engineering from the University of Pittsburgh and a master’s in Public Management (Health Systems IT) from Carnegie Mellon University. While obtaining his BS degree, Zini did an internship in hospital consulting and became immediately interested in healthcare automation as a way to solve hospital inefficiencies. Zini went on to become the Vice President of Sales and Marketing for Automated Healthcare, which developed the first robotic medication dispensing system for hospitals (ROBOT-Rx) and was acquired by McKesson for $67 million. Before joining and investing in Aethon, Zini was Senior Vice President of sales and marketing for TechRx, one of the largest providers of software solutions to the pharmacy industry, which was sold to NDC Corporation for over $200 million. Originality/value – Zini has been leading the technology revolution in hospital automation for more than 25 years. His contributions to technology-driven companies have led to acquisitions worth more than a quarter of a billion dollars. Zini owns several patents in medication-dispensing technology, and is credited with the development of key methodologies in quantifying the value proposition for several technology platforms deployed in hundreds of hospitals across the country.

Abstract Background: The zinc finger transcription factors, Aiolos (IKZF3) and Ikaros (IKZF1) were identified as lenalidomide (LEN) and pomalidomide (POM)-induced substrates of the cereblon (CRBN)-dependent Culin4 E3-ligase complex. While recent studies suggest that the anti-proliferative activity of LEN and POM in multiple myeloma (MM) cell lines in vitro is due in part to the targeted ubiquitination and subsequent proteasomal degradation of Aiolos and Ikaros, the downstream molecular mechanisms remain unknown. Using inducible shRNA-mediated knockdown combined with kinetic analyses, we systematically investigated the biological mechanisms associated with the degradation of Ikaros and Aiolos in MM cell lines that are sensitive to or have acquired resistance to LEN and POM. Results: In MM1.S and U266 MM cell lines stably engineered with doxycycline (DOXY)-inducible shRNAs, knockdown of either Ikaros or Aiolos showed a reduction in cell proliferation (80%-90%) as measured by 3H-thymidine incorporation after a 4 day treatment with DOXY. We demonstrated that this anti-proliferative effect is inherently tied to and precedes the induction of apoptosis, which was maximized (60%-80% AnnV+/ToPro3+) 5 days following Aiolos or Ikaros knockdown compared with a control shRNA. shRNA-mediated knockdown of Aiolos or Ikaros was furthermore associated with decreases in both c-Myc and IRF4 protein expression levels (70%-90% and 60%-80%, respectively) that were maximized by day 4. In turn, shRNA knockdown of either c-Myc or IRF4 elicited anti-proliferative (> 80% inhibition) and pro-apoptotic (50%-80%) responses as early as 48hrs after shRNA induction. These data suggest that the reduction of c-Myc and IRF4 protein levels downstream of Aiolos and Ikaros degradation account for the apoptotic effect and marks the onset of the cytotoxic response induced by LEN and POM in MM cells. To define the temporal order of events involving Aiolos, Ikaros, c-Myc and IRF4 in more detail, kinetic experiments following shRNA-mediated knockdown in parallel with drug treatments were performed. Data from these experiments showed that there is a distinct kinetic order of both LEN- and POM-mediated effects, initiated by immediate targeted degradation of Aiolos and Ikaros (within 90 min), followed by a decrease in c-Myc levels (24-48 hrs) with subsequent IRF4 downregulation (48-72 hrs), and finally, resulting in programmed cell death (3-5 days). Importantly, DOXY washout experiments, resulting in re-accumulation of Aiolos or Ikaros at early time points (24 hrs) partially overcame the antiproliferative effects of the shRNA-mediated knockdown of either target. Interestingly, upon the onset of c-Myc downregulation (24-48 hrs), the commitment to cell death could no longer be reversed in our experiments. Further, we generated MM1.S and U266 cells with acquired resistance to POM (10 µM; also cross-resistant to LEN) (MM1.S/PomR and U266/PomR , respectively), in which CRBN protein expression is substantially decreased (> 90%). Consequently, in these resistant cell lines, neither Aiolos nor Ikaros are degraded in the presence of LEN or POM. However, bypass of CRBN-dependent Aiolos degradation by DOXY-induced knockdown rescued c-Myc and IRF4 downregulation and concomitant inhibition of growth (90% and 60%, respectively), suggesting that resistant MM cells with acquired CRBN loss remain dependent on Aiolos and Ikaros. Conclusions: For the first time, our studies showed that degradation of Aiolos and Ikaros sets up a molecular sequence of events culminating in programmed cell death in MM cells. Our mechanistic studies showed that c-Myc is a key intermediate factor whose downregulation is a rate-limiting step for the transcriptional downregulation of IRF4 as well as for the commitment to cell death. Taken together, our results demonstrate a molecular sequence of events underlying the mechanism of action of cytotoxicity of LEN or POM in MM cells. Quantitative measurements of Aiolos and Ikaros degradation, and c-Myc and IRF4 downregulation in clinical samples would help validate these findings. Disclosures Bjorklund: Celgene Corp: Employment, Equity Ownership. Havens:Celgene Corporation: Employment, Equity Ownership. Hagner:Celgene Corp: Employment, Equity Ownership. Gandhi:Celgene Corp: Employment, Equity Ownership. Wang:Celgene Corp: Employment, Equity Ownership. Amatangelo:Celgene Corp: Employment, Equity Ownership. Lu:Celgene Corp: Employment. Wang:Celgene Corp: Consultancy. Breider:Celgene Corp: Employment. Ren:Celgene Corp: Employment. Lopez-Girona:Celgene Corp: Employment, Equity Ownership. Thakurta:Celgene Corp: Employment, Equity Ownership. Klippel:Celgene Corp: Employment. Chopra:Celgene Corp: Employment, Equity Ownership.

Abstract Background: U2AF1 forms a heterodimer for the recognition of the 3' splice site during pre-mRNA splicing. Somatic U2AF1 mutations are present in approximately 10% of MDS patients. Most U2AF1 mutations are recurrent at 2 highly conserved hotspots, while non-canonical mutations are rare. U2AF1S34 and U2AF1Q157 mutations map within the zinc finger domains of the protein, resulting in distinct downstream effects. We have previously shown that U2AF1Q157 mutant patients have distinct splicing patterns compared to U2AF1WT with a set of misspliced targeted genes, including ARID2 and EZH2. In contrast, recent work focusing on S34 suggests a distinct subset of misspliced genes, including ATG7 (Park SM, Molecular Cell, 2016). The biological and clinical implications of these 2 distinct mutations are unknown. We investigated the differences between these mutations with respect to clinical outcomes and molecular background, including their impact on clonal architecture. Methods: We first collected molecular and clinical data on a cohort of 1700 patients with myeloid neoplasms (median follow up 1.0 year, range 1-5 years), median age was 65 years (range, 11-93). Targeted deep sequencing of a panel of frequently mutated genes (64) was applied. Our analyses included somatic mutational patterns, clonal hierarchy, and mutational correlation of the cohort of patients with U2AF1S34 and U2AF1Q157 and those without mutations in this gene. U2AF1 mutations were found in 5% (78/1700) of patients, all of them were missense and in a heterozygous configuration. Results: Both mutations were equally distributed in the cohort: U2AF1S34 (45%, 35/78), and U2AF1Q157 (46%, 36/78). Other mutations (Q84, E124, E152, and R156) were detected at a lower frequency (9%). We then dissected the clonal hierarchy of both U2AF1 mutations and found that 44% (34/77) were ancestral while 56% (43/77) were secondary. In MDS, most U2AF1 mutations (77%, P=.002) were dominant, while subclonal U2AF1 mutations were evenly distributed between the subentities. U2AF1S34 or U2AF1Q157 were equally likely to be dominant (21% vs. 27%; ancestral events; P=.09, respectively). Similarly, S34 and Q157 mutant clones had similar median variant allele frequencies (3-52% vs. 8-64%). U2AF1 S34 mutant cases had similar OS to patients carrying U2AF1Q157 (N=35 vs. N=36; 10 vs. 15 months; P=.209; LogR=.65). When we compared the impact of ancestral vs. secondary U2AF1S34 and U2AF1Q157 we found that MDS patients carrying ancestral U2AF1 mutations had a shorter OS compared to MDS patients carrying secondary U2AF1 patients (N=26 vs. N=18; 13 vs. 34 months; LogR=.04). Of note, ancestral U2AF1S34 patients had shorter OS compared to ancestral U2AF1Q157 patients (13 vs.11; 10 vs.15 months; P=.03; LogR=.86). Given these differences, we also investigated the mutational spectrum of U2AF1MUT patients. Cross sectional analysis identified that the top genes mutated in the U2AF1 mutant cohort were: ASXL1 (26%), BCOR/L1 (15%), TET2 (13%), DNMT3A and PHF6 (12%), ETV6 (10%), RUNX1 and STAG2 (9%), and SETBP1 (8%). Transcriptional factor and DNA-methylation genes were predominantly mutated in U2AF1MUT patients (35% and 24%, respectively). Exploring the association between S34/Q157 vs. other gene mutations, S34 co-occurred with BCOR/L1 mutations (P=.007, 24%), while Q157 mutations co-occurred with ASXL1 (P=.003, 44%) irrespective of their rank in the clonal hierarchy. When S34 was the dominant mutation, secondary mutations included ETV6, BCOR, and CUX1. In contrast, when Q157 was the ancestral event, secondary mutations included ASXL1 and DNMT3A. Subclonal S34 occurred in the context of ancestral RUNX1, BCOR/L1, CUX1 and DNMT3A, while subclonal Q157 followed ancestral ASXL1, EZH2, PHF6 and TET2. Conclusion: In sum, U2AF1S34 and U2AF1Q157, consistent with their differential missplicing consequences, create a distinct molecular milieu leading to differences in clinical outcomes. Disclosures Makishima: The Yasuda Medical Foundation: Research Funding. Carraway:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Celgene: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees.

The development of efficient materials for heat storage has become recently a popular research topic as amount of energy gained from solar power depends significantly on day and night cycle. That's why the right choice of material for heat storage directly affects the utilization efficiency of solar thermal energy. Research on heat storage materials nowadays focuses on phase change materials (PCMs) enabling repeatedly utilize the latent heat of the phase transition between the solid and liquid phase. Most currently used PCMs have low thermal conductivity, which prevents them from overcoming problem of rapid load changes in the charging and discharging processes. To overcome this obstacle and to obtain excellent heat storage possibility, various techniques have been proposed for enhancing the thermal conductivity of PCMs, such as adding metallic or nonmetallic particles, in-corporating of porous or expanded materials, fibrous materials, macro-, micro-, or nanocapsules, etc.The authors of this study report particularly the huge potential of oxide nanoadditives, such as titania (TiO2), alumina (Al2O3), silica (SiO2) and zinc oxide (ZnO), that are even in small quantities (up to 3 wt.%) able significantly to enhance the heat storage characteristics of conventional PCMs. Moreover, the microstructure of the granules produced by recycling of aluminum scrap refers to the possibility of their utilizing for the purpose of low cost solutions enabling to increase the thermal conductivity of PCMs. The above mentioned technical solutions are therefore the important keys to successful commercialization of materials for latent heat storage in future building industry.

Zarqa Nawaz is a Canadian Muslim filmmaker who lives with her family inRegina, Saskatchewan. There are any number of comments that could beinserted at this point. Having spent time on both the Saskatchewan andManitoba prairies, I note only that Zarqa is developing a television series forthe Canadian Broadcasting Corporation entitled “Little Mosque on thePrairie.” She has made two earlier short films, BBQ Muslims and DeathThreat. Information about those films, as well as about Zarqa, can be foundon her website, Fundamentalist Films, available at www.fundamentalistfilms.com.Me and the Mosque, her first documentary, is distributed by the NationalFilm Board of Canada. The film is directly related to her own concerns as aMuslim woman, namely, as to space available to her in the mosque. The filmbegins on a light-hearted note (as does her web site, with the tag line of “puttingthe fun back into fundamentalism”) with Muslim comic Azhar Usmanjoking about the lack of appropriate space available in mosques for Muslimwomen.The documentary traverses mosques in Canada and the United States,such including places as Aurora, Illinois; Mississauga, Ontario; Winnipeg,Manitoba; Regina, Saskatchewan; Surrey, British Columbia; and Morgantown,West Virginia. It includes the voices of established scholars, amongthem Asma Barlas, Umar Abd-Allah, and Aminah McCloud, alongside thenewer scholarly voices of Aisha Geissinger, Jasmine Zine, and Itrath Syed.In addition, there is a wide range of interviews with people from the Muslimcommunity, from such activists as Asra Nomani and Aminah Assilmi to suchscholars as Abdullah Adhami and Tareq Suwaidan.As mentioned above, the film begins on a humorous note with the comedyof Azhar Usman (of “Allah Made Me Funny” fame). However, what hejokes about, the nice “dungeons” that many people mention when they talkabout the basements where some mosques give space to women, is no laughingmatter. The film then moves to the mosque in Aurora to begin its discussionof these issues. I would like to think that this is Zarqa’s subtle homageto another Canadian filmmaker, Mike Myers, who bases his fictional character,Wayne Campbell, in Aurora. Zarqa then mentions her upbringing inToronto and contrasts the mosque that she attended (the Jami’ Mosque) while ...

Momelotinib (MMB) is a potent, selective, orally-bioavailable, small-molecule inhibitor of JAK1, JAK2 and ACVR1 being developed for the treatment of intermediate and high risk myelofibrosis (MF). Systemic inflammation integral to the pathogenesis of MF leads to increased ACVR1 activity which in turn increases secretion of hepcidin, resulting in perturbed iron homeostasis and an iron-restricted anemia (Physiol Rev. 2013;93:1721-41, Am J Hematol. 2014;89:470-9). MMB's inhibition of ACVR1, unique amongst the JAK inhibitor (JAKi) class, leads to a reduction of hepcidin, restoring iron homeostasis and RBC production and alleviating anemia and transfusion dependency (TD). Chronic, progressive anemia is the key hallmark feature of MF; anemia and TD are strongly predictive of reduced survival (Am J Hematol. 2013;88:312-6). MMB is the only clinical stage JAKi to possess potent ACVR1 inhibitory activity, resulting in improvement of anemia in contrast to ruxolitinib (RUX) which results in worsening. The SIMPLIFY-1 (S1) trial, a double-blind, active-controlled Phase 3 study in which 432 patients received randomized treatment with MMB or RUX for 24 weeks was previously reported (JCO. 2017;35:3844-50). In addition to a significant reduction in splenomegaly and improvement in constitutional symptoms, the study demonstrated that patients in the MMB arm achieved nominal-statistical significance for all anemia endpoints tested, including a higher rate of transfusion independence (p<0.001) and lower rates of TD (p=0.019) at Week 24, compared to patients on RUX, consistent with MMB's pro-erythropoietic effect. Overall, a demonstrably decreased transfusion requirement was noted in patients who received MMB vs RUX. Since transfusion burden is of significant concern to clinicians and patients, to better understand the dynamics of RBC transfusions we further examined the S1 data through statistical models utilizing a variety of novel anemia benefit endpoints including time until transfusion and overall intensity of transfusions across time. The proportions of patients with 0 and 4 transfusions were calculated and time-to-event analyses examining time-to-first and time-to-fifth units transfused also conducted. Since transfusions typically comprise 2 units, the fifth unit transfused represents a de facto third transfusion event. The number of units transfused were also considered to be recurrent events and examined with and without patients' baseline characteristics as covariates. Finally, a mixture model, based on a zero-inflated negative binomial (ZINB) distribution fit to the transfusion data, was employed to compare between the treatment groups the proportions of subjects with zero transfusion burden and the mean transfusion rates. Kaplan-Meier estimates of the proportion of patients who did not require any units transfused during the 24 week randomized treatment period were 73% and 46% for MMB and RUX respectively (p<0.0001; Figure 1), while the proportion of patients requiring 4 or fewer units were 83% and 62% (p<0.0001). When examining units transfused as recurrent events, patients receiving MMB possessed a hazard ratio of approximately one-half that for patients on RUX (HR 0.522; p<0.0001) for models both with and without patients' baseline characteristics as covariates. The ZINB covariate model demonstrated that MMB increased the odds of having zero units transfused in the first 24 weeks by a factor of 9.3 (p<0.0001) vs RUX. Taken together, the novel dynamic and time-to-event analysis methods described are relevant and informative additions to standard measures of transfusion burden in patients with MF. The results of these analyses allow more detailed description of MMB's differentiated anemia benefit as compared to RUX in a double-blind study of JAKi-naïve patients. These results when combined with additional data from the SIMPLIFY studies demonstrate that MMB is able to address the three hallmark features of MF, namely anemia, constitutional symptoms and splenomegaly, differentiating it from other JAK inhibitors. The benefit of MMB in reducing transfusion burden will be further evaluated in MOMENTUM, a future Phase 3 study of MMB in MF patients. In addition to assessment of constitutional symptoms, anemia and splenomegaly, MOMENTUM will provide opportunity to further evaluate associations between anemia benefit and patient reported measures of clinical benefit. Disclosures Mesa: Promedior: Research Funding; Gilead Sciences: Research Funding; Galena Biopharma: Consultancy; AbbVie: Research Funding; Incyte: Other: travel, accommodations, expenses, Research Funding; Genotech: Research Funding; CTI: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene Corporation: Research Funding; Sierra Oncology: Consultancy; PharmaEssentia: Research Funding; Genentech: Consultancy; NS Pharma: Research Funding; Pfizer: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; LaJolla: Consultancy; Samus: Research Funding; Shire: Honoraria; Baxalta: Consultancy. Catalano:Celgene: Other: Travel support (ASH 2018). Cervantes:Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Gotlib:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Promedior: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deceiphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiladjian:Novartis: Honoraria, Research Funding; Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Coart:IDDI: Consultancy, Employment. D'Hollander:IDDI: Consultancy, Employment. Donahue:Sierra Oncology Inc.: Employment. Kowalski:Sierra Oncology Inc.: Employment.

Abstract GALVALUME is a sheet steel product having a coating of an aluminum-zinc alloy applied by a continuous hot dipping process. It combines the corrosion resistance, high temperature oxidation resistance and heat reflectivity of aluminum coatings with the formability and galvanic protection of zinc coatings. This datasheet provides information on composition, physical properties, hardness, and tensile properties. It also includes information on corrosion resistance as well as forming, joining, and surface treatment. Filing Code: Al-257. Producer or source: Bethlehem Steel Corporation.

This paper examines the process and methodological aspects of implementing online X-ray fluorescence monitoring of ore in terms ofits silver, cadmium, zinc, lead, molybdenum, and iron grade at the process conveyors at Balkhash and Karagaily Concentrators andthe main conveyor of the Nurkazgan underground mine operated by Kazakhmys Corporation LLC. The research was complicated bythe need to: a) ensure reliable measurement of silver and cadmium in the range of 1+ ppm, molybdenum in the range of 10+ ppm, aswell as copper, zinc, lead, and iron in the ore size class –300 mm; b) implement monitoring of the grade of these elements (except molybdenum) at Balkhash Concentrator in the waste slag of Balkhash Copper Smelter, characterized by a very complex elemental matrix.A modification of the ore monitoring station RLP-21T (by Aspap Geo LLC, Alma-Ata) was developed, implemented, and thoroughlytested for online monitoring of low-grade silver ore flows. Energy dispersive X-ray fluorescence method was adopted for ore assays.Instrument spectra were measured every second. Silver, cadmium, and molybdenum grade was calculated based on 40 measurements,copper, zinc, lead, and iron grade – based on 20 measurements.

Monodisperse zinc oxide (ZnO) nanoparticles were synthesized using ultrasonically atomized precursor mist in simple chemical route at low temperature. Analytical grade sodium hydroxide and zinc chloride were dissolved in 100 ml methanol. Zinc chloride precursor solution was converted into very fine mist (atomized) using a nozzle (Sono-Tek Corporation, U.S.A.) operated at ultrasonic frequency of 120 KHz. Fine mist droplets were added slowly (50ml/ hour) into sodium hydroxide solution in 2 hours. The NaOH solution in beaker turned slowly into white product due to addition of zinc chloride. The white product was kept in constant temperature bath at 90°C for 3 hours. The white product was washed five times using double distill water and dried in oven for 2 hours. Different powder samples were synthesized using same procedure by changing the molarity of sodium hydroxide keeping the molarity of zinc chloride and other preparative conditions same. The structural, microstructural, thermal and optical properties of fine powders were analyzed using X Ray Diffractometer, Scanning Electron Microscopy, Simultaneous Thermal Analyzer, UV-Vis Spectroscopy and Photoluminescence Spectroscopy. Fine ZnO nanorods, elongated and spherical nanoparticles were observed due to change in molarity of NaOH. The results are discussed and interpreted.

AbstractTransport of sulphuric acid in the presence of zinc sulphate through the anion-exchange membrane Neosepta-AFN (Astom Corporation, Japan) was studied in a two-compartment counter-current dialyzer with single passes at steady state. The following characteristics were used to characterize the dialysis process: recovery yield of acid, rejection coefficient of salt, and permeability coefficient of the membrane. In case of the H2SO4 + ZnSO4 mixture, permeability of the membrane was quantified by four phenomenological coefficients which are functions of acid and salt concentrations in the feed. They were determined by numerical integration of differential equations describing the concentration profiles of both components in both compartments, which was combined with an optimizing procedure.

Abstract ZAMAK-5 has moderately greater hardness, strength and creep resistance than the most widely used general purpose zinc die casting alloy, ZAMAK 3 (See Alloy Digest Zn-1, September 1991). This datasheet provides information on composition, physical properties, hardness, elasticity, tensile properties, and compressive and shear strength as well as fracture toughness and fatigue. It also includes information on corrosion resistance as well as casting, heat treating, machining, and joining. Filing Code: Zn-2. Producer or source: Noranda Sales Corporation. Originally published as Zamak-5, May 1954, revised February 1992.

Abstract ZAMAK 3 is the most widely used general purpose zinc-base die casting alloy. It provides an excellent combination of strength and ductility. It has good impact strength. It is the designer's first choice for die casting applications. This datasheet provides information on composition, physical properties, hardness, tensile properties, and compressive and shear strength as well as fracture toughness and fatigue. It also includes information on corrosion resistance as well as forming, heat treating, machining, and joining. Filing Code: Zn-1. Producer or source: Noranda Sales Corporation. Originally published December 1953, revised August 1966, revised September 1991.

Abstract ZA-8 is a zinc-base foundry alloy capable of being sand, permanent mold gravity or die cast (hot-chamber machine). ZA-8 should be the first choice when considering die casting the ZA family (3 alloys) due to its cost effective hot-chamber castability. This datasheet provides information on composition, physical properties, hardness, elasticity, tensile properties, and compressive and shear strength as well as fracture toughness, creep, and fatigue. It also includes information on corrosion resistance as well as casting, heat treating, machining, joining, and surface treatment. Filing Code: Zn-35. Producer or source: Noranda Sales Corporation. Originally published November 1980, revised October 1991. See also Zn-48, January 1990.

Abstract This study consisted of three 5-wk experiments to test the effects of administering Zinpro-LQ (Zinpro-LQ, Zinpro Corporation, Eden Prairie, MN) for different time intervals in stressed broilers, pullets, and layers. Treatments included: nonstressed control (NC), stressed control (SC), stressed and supplemented Zinpro-LQ for 14 d prior to stressor (S1), 10 d prior (S2), 7 d prior to and 7 d during stressor (S3), and 5 d prior (S4). Birds included 1-d-old Cobb 500 male broilers (Experiment 1), 7-wk-old white Leghorn pullets (Experiment 2), and 50-wk-old white Leghorn layers (Experiment 3). All stressed birds were vaccinated against Newcastle Disease Virus (NDV) on day 28 and exposed to random feed and water withdrawal days 28 to 35 for 6 h/d. Pullets were beak trimmed on day 21, and layers were heat stressed days 28 to 35. Blood was sampled on day 35 to determine plasma chemistry, corticosterone (CORT), anti-NDV antibody titer, and heterophil/lymphocyte (H/L) ratio. Mortality, feed and water consumption, and BW were also recorded. In Experiment 1, CORT and H/L ratio were highest in SC (P &lt; 0.05). In Experiment 2, CORT was higher in SC than S4 (P &lt; 0.05) while all other treatments were statistically intermediate. NDV titer was lower in SC than S4 while all other treatments were statistically intermediate. Treatment differences were also observed for H/L ratio, and plasma uric acid and cholesterol in Experiment 2. In Experiment 3, treatment differences were observed for H/L ratio, plasma glucose, sodium, and chloride. H/L ratio was lower in NC, S1, and S4 compared with SC (P &lt; 0.05); and NC and S1 were lower than S2 (P &lt; 0.05). In conclusion, dietary inclusion of zinc AA complex for any length of time prior to a stressor helped reduce measures of stress in broilers. The S1 and S4 treatments helped reduce stress and improve humoral immune response in pullets and layers.

Abstract The quality of drinking water source remains as a major concern in areas of developing and underdeveloped countries worldwide. The treatment and supply of drinking water in Rwanda are carried out by Water and Sanitation Corporation, a state-owned public company. However, it is not able to supply water to all households. Consequently, the non-serviced households depend on natural water sources, like springs, to meet their water requirements. Nevertheless, the water quality in these springs is scarcely known. Therefore, this study assessed and compared metal elements in drinking water sources in the dry and rainy seasons in 2017 using the contamination degree, metal index, and geographic information systems to reveal the spatial distribution of water quality within the considered water sources of springs in Rwanda. The samples were collected monthly from nine water sources of springs and the measured elements are aluminium, calcium, copper, iron, manganese, and zinc. The metal index indicated that during the dry season and rainy season, the sites of Kibungo (1.10 and 1.26) and Kinigi (1.01 and 1.54) have assessed a metal index which is higher than 1. Thus, the water quality of those sites was getting the threshold of warning. The analysis indicated that pollutants are easily transported into water bodies during the rainy season in urban and rural areas to a greater extent than during the dry season .

Abstract Trace minerals are known to play important roles in early embryo development. The study objective was to determine effects of trace mineral source on heifer reproductive performance. Beef heifers (n = 129) were randomly assigned to one of two treatments. From weaning through breeding, all heifers were individually fed a basal diet supplemented with cobalt (Co), copper (Cu), manganese (Mn), and zinc (Zn) either from organic sources (COMP; Cu, Mn, and Zn amino acid complexes and Co glucoheptonate; Availa-4, Zinpro Corporation, Eden Prairie, MN) or inorganic sources (INORG; Cu, Mn, and Zn hydroxychlorides; Intellibond C, M, and Z, Micronutrients, Indianapolis, IN) and Co as CoSO4. Blood samples and a reproductive tract score (RTS) were collected to determine pubertal status. All animals were synchronized and artificially inseminated. Pregnancy status was determined by lymphocyte gene expression, circulating concentrations of pregnancy-associated glycoproteins (PAGs), and by transrectal ultrasonography after artificial insemination. Embryonic loss was defined as when a previously pregnant animal was subsequently diagnosed not pregnant. Data were analyzed using the MIXED procedure in SAS. Puberty (P = 0.44), pelvic area (P = 0.74), RTS (P = 0.49), and estrus expression (P = 0.82) were not influenced by treatment. There was no effect of treatment (P = 0.37) or treatment by time (P = 0.19) on pregnancy, but there was a tendency (P = 0.13) for decreased embryonic loss among COMP heifers (27 ± 6%) compared to INORG heifers (38 ± 6%). There was a treatment by pregnancy status by time interaction (P &lt; 0.01) on circulating PAG concentrations with PAG concentrations tending (P = 0.08) to be greater on day 25 among heifers in the COMP treatment compared to heifers in the INORG group. In summary, source of trace mineral did not affect puberty, RTS, pelvic area, or overall pregnancy success, but feeding complexed trace minerals tended to increase circulating PAG concentrations and embryo survival.

Recently, on the alt.zines newsgroup there was a discussion that centred around the perception that zines were experiencing a decline in popularity. This followed a period, at least in the US, of intense scrutiny of zines and their editors by the corporate mass media. For a brief time, newsstands and distributors had been willing to stock these non-commercial independent publications -- with their sometimes illegible fonts, cut'n'paste layouts, and personal diatribes -- alongside the glossy covers and slick production values of Rolling Stone and Vanity Fair. After commercial magazines had exhausted the novelty factor of zines and their editors, a reluctance by commercial enterprises to continue to sell zines ensued. Following the thread "**Zines Fading from Popularity? Why?" some contributors to the newsgroup wondered whether the alleged decrease in interest reflected an overall decline in the standards of zines being made. While other contributors offered evidence to refute an emergent lack of interest in zines, 'Kris from Menace Publishing & Manufacture' suggested that "zines are a very adolescent medium, and I think a lot of people just outgrow them, both producers and readers" ('Kris'). Kris's point in using the term adolescent was to account for a presence among zine editors of those who were not committed to producing zines in the long term. He employs a notion of adolescence as a developmental stage at the end of which one becomes an adult. Although it would appear that Kris makes zines, he uses adolescence as a pejorative term to describe them as the expression of a transient stage of human development which it is expected one will leave behind. Kris's linking of zines and adolescence as a developmental stage becomes complicated while there are people who don't outgrow zines. Jeff Potter responds directly to Kris's analogy between adolescence and zines when he writes: I like the 'playing for keeps' aspect of true art. The 'it's just a phase' sector is perhaps the weakening one. Altho I have nothing against ephemera or one offs or whatever. Pop, kiddy, groupie stuff tho: ferget it [sic]. (Potter) While Potter does nothing to dispel the prevailing societal disdain for adolescents and youth in general -- he trivialises their zines as "pop" and "kiddy" --, he introduces another understanding of transience in his reference to "one-offs" and "ephemera", one that is not so easily dismissed as when the association with adolescence is made. The use of 'adolescent' to dismiss some zines, while valorising the ephemeral characteristic of others, is intriguing. In response it might be argued that adolescence offers a model for zines and the identities and communities that surround them; evolving structures that are also characteristic of ephemeral cultural products. In the Brisbane-based Australian zine Fried Trash Tabouli, Cathy Tabouli considers the notion of adolescence as a pejorative description applied to zines and people who make them: I mean this maybe the last fried trash tabouli cos a kinda friend got me thinking about how fucked zines are and how kiddie they are but hell I'm a kid! I'm a kid who just so happens to be of adult age and responsibility. I realised how stupid their opinion can be... (Tabouli, n.pag.) This example shows how Tabouli reappropriates the state of being "kiddie" and takes it with her into adulthood. The conclusions that Tabouli draws, which enable her to adopt adolescence as an ongoing way of being in the world, are evocative of the understanding of adolescence articulated by Julia Kristeva. Kristeva speaks about adolescence as a period when having a subjectivity-in-process is socially acceptable. As a teenager, one is able to restlessly reject role after role, to try on a number of identities, each of which is lived as authentic. An adolescent represents, "naturally", "a crisis structure within the ideal and consistent law" of the social world (Kristeva 136); the adolescent is able to transgress the boundaries of difference within society without incurring penalty. Kristeva describes the adolescent as an open-structure personality and she suggests that the on-going process of the adolescent stage of development is an ideal model for writing because through the practice of writing one is able to explore the possibilities of identity without encountering judgment. As a community that is organised around writing it is possible to identify the open-structure of adolescence in zines -- not just in the youthfulness of many (although certainly not all) of those who write and read them, but also in the constant process of exploring ways of being in the world that fill their pages. On a nominative level one can quickly identify instances of a restless rejection of roles in the way that many zine editors, through the pages of their zines, adopt new names, and thus "a new living identity" (Kristeva 137). In The Life and Times of Mavis McKenzie the editor, 'Jason', pretends he is an elderly woman, Mavis McKenzie. Mavis sends letters to local councils, celebrities and businesses exercising her civic duty to hilarious effect. That Mavis receives replies to her ridiculous enquiries and outrageous opinions exposes the inanity of many bureaucracies and (star) systems, and enables 'Jason' to critique current events and to make fun of "the never-ending procession of dumb celebrities and companies" ('Jason'). Further examples of new identities configured through producing a zine are evident in pseudonyms like Kylie Gusset of the e-zine Gusset; Kylie Purr, formerly of PURRzine and now Kat Pounce; Chris Dazed of Dazed and Swarming and Coughing Up Legomen; and Flea, who in her transition from the seminal zine Grot Grrrl to Thunderpussy has adopted the latter title as a surname. The association of many zine editors with more than one zine title is worth noting in a discussion of the open-structured adolescent quality of zines. In the 'Idiotorial' of Kat Pounce/PURRzine #4 Kylie Purr explains the reasoning behind the name change of her zine: soooo much has changed!! A new name has been adopted, for the purpose of separating my 2 projects, zine-purr and band-purr, but Purr broke so its [sic] just a fresh exciting new start. I've lived in three more houses since #3, but I am now, in theory, settled for awhile [sic]. In this shocking era of tranquility I have established a herb garden, honed my drawing skills, learnt to touchtype (30wpm and counting!!), expanded my cooking repetoire [sic] and deliberated over a musical future. I laughed at the State Rail Authority and their free entry to central (via Country terminal ramp) for several moths [sic]. I became much louder and more frequent in my verbal abuse of TV. I became happier and more bitter. I've gotten really sick of loser fuck ups, no more patience with that I'm afraid. I met a lot of really nice people who aren't loser fuck ups so I just hang out with them!! (Purr, n.pag.) Although the name change in Purr's zine was initially for pragmatic reasons, it came to represent a substantial shift, not only in terms of the number of residences she lived in over eighteen months, but also in her perspective on life. Chris Dazed cited a similar evolution in his perspective in a conversation I had with him at the recent National Young Writers Festival in Newcastle. Chris's decision to abandon Dazed and Swarming and start Coughing Up Legomen was motivated by a deeper philosophical understanding that had emerged as a consequence of beginning university. Chris felt that Dazed and Swarming zine could no longer contain or express the evolution of his self and ideas. While some zine editors accommodate a shift in identity by leaving one zine and beginning another, others such as 'Jason' from The Life and Times of Mavis McKenzie make more than one zine -- a multiplicity of writing which captures in print an adolescent structure of subjectivity that is constantly in process or on trial; in a state of (r)evolution. In 'Jason's' case additional zines are one-offs of more personal writing. More recently he has been involved in producing a zine on electronic pop music in collaboration with some friends. Often the parameters of other people's zines provide the space for the articulation of a different voice. A negative use of this willingness in zines to accept contributions from outside sources is related in a US zine, Escargot: Leslie Gaffney (Popwatch) told us about another zine editor who once offered to write reviews for Popwatch because he decided reviews were too passé for inclusion in his own zine, but if he wrote reviews for another zine, he could protect his own editorial principles and still get the free promos. (Billus & McKinney, n.pag.) While this example is instructive, in an Australian context it also appears to be atypical. Generally, it might be said that the manner in which zine editors avail their pages to a constant input of ideas from many individuals and sources (contributions and stealing images etc.) goes beyond an expression of multiple and evolving identities towards facilitating an aesthetic, and a community that is predicated on the open-structure personality of the adolescent. While aesthetically zines are never only one thing; the forms zines take are many and varied: photocopied and glossy, illegible and streamlined, within their pages there is a genuine exchange between writers and readers. In zines feedback moves beyond the mere printing of letters to the editor, to blur, perhaps even abolish, the distinction between a passive reader and an active producer. The idea that anyone, even with the most minimal of resources -- scissors, glue, pens and paper -- can create a zine eliminates the barriers which restrict access to other, more costly forms of cultural production (Simon Turnbull of Some Underground Machine). Those who contributed to the alt.zines newsgroup thread mentioned earlier express an appreciation of the role of the 'newbie', the new zine editor. New readers and fans that become writers and editors sustain the zine community. While some zine editors may go on to pursue other interests, or as in the US begin to make money from their zines, the reasons people do zines will, as Seth Friedman of Factsheet Five has pointed out, ensure that new people constantly enter into the zine community ("Zine and Not Herd"), to "push on ... jaded old-timers", and "question [the existing] structure" (Crye). To this end, zines are an adolescent medium; they are predicated on, and facilitate an open-structure (r)evolutionary mode of being in the world. References Billus, J., and K. McKinney. "A Zine in the Hand Is Worth Two in the Putsch... Or, What's Really Going On in the Zine Revolution." Escargot Summer 1997: 14-18. Crye, Michael. <mcrye@ket.org> "Re: **Zines fading from popularity? Why?" 5 June 1998 <alt.zines>. Guillory, Sean. <guillory@ix.netcom.com> "**Zines fading from popularity? Why?" 5 June 1998 <alt.zines>. 'Jason'. "Re: hmmm, don't know really." Personal email. 7 Oct. 1998. 'Kris from Menace Publishing & Manufacture'. <menace@ziplink.net> "Re: **Zines fading from popularity? Why?" 5 June 1998 <alt.zines>. Kristeva, Julia. New Maladies of the Soul. New York: Columbia UP, 1995. Potter, Jeff. <jp@glpbooks.com> "Re: **Zines fading from popularity? Why?" 5 June 1998 <alt.zines>. Purr, Kylie. Kat Pounce #4 (n.d.). Tabouli, Cathy. Fried Trash Tabouli #4 (n.d.). Turnbull, Simon. Personal interview. 8 Oct. 1998. "Zine and Not Herd." Attitude. Australian Broadcasting Corporation. ABC, Brisbane. 27 Aug. 1994. Citation reference for this article MLA style: Kirsty Leishman. "Being (R)evolutionary: A Consideration of the Adolescent Nature of Zines." M/C: A Journal of Media and Culture 1.3 (1998). [your date of access] <http://www.uq.edu.au/mc/9810/zine.php>. Chicago style: Kirsty Leishman, "Being (R)evolutionary: A Consideration of the Adolescent Nature of Zines," M/C: A Journal of Media and Culture 1, no. 3 (1998), <http://www.uq.edu.au/mc/9810/zine.php> ([your date of access]). APA style: Kirsty Leishman. (199x) Being (r)evolutionary: a consideration of the adolescent nature of zines. M/C: A Journal of Media and Culture 1(3). <http://www.uq.edu.au/mc/9810/zine.php> ([your date of access]).