Academic literature on the topic '610.73S 88'

Intravenous injection of galanin increases plasma growth hormone (GH) and prolactin (PRL) concentrations. In the rat, the effects of galanin on GH appear to be mediated via the hypothalamic galanin receptor GAL-R1, at which galanin-(3—29) is inactive. In contrast, the effect of galanin on PRL is mediated via the pituitary-specific galanin receptor GAL-RW, at which galanin-(3—29) is fully active. We investigated the effects of an intravenous infusion of human galanin (hGAL)-(1—30) and -(3—30) on anterior pituitary hormone levels in healthy females. Subjects were infused with saline, hGAL-(1—30) (80 pmol ⋅ kg− 1 ⋅ min− 1), and hGAL-(3—30) (600 pmol ⋅ kg− 1 ⋅ min− 1) and with boluses of gonadotropin-releasing hormone, thyrotropin-releasing hormone, and growth hormone-releasing hormone (GHRH). Both hGAL-(1—30) and -(3—30) potentiated the rise in GHRH-stimulated GH levels [area under the curve (AUC), saline, 2,810 ± 500 vs. hGAL-(1—30), 4,660 ± 737, P < 0.01; vs. hGAL-(3—30), 6,870 ± 1,550 ng ⋅ min ⋅ ml− 1, P < 0.01]. In contrast to hGAL-(1—30), hGAL-(3—30) had no effect on basal GH levels (AUC, saline, −110 ± 88 vs. hGAL 1—30, 960 ± 280, P < 0.002; vs. hGAL-(3—30), 110 ± 54 ng ⋅ min ⋅ ml− 1, P = not significant). These data suggest that the effects of galanin on basal and stimulated GH release are mediated via different receptor subtypes and that the human equivalent of GAL-RW may exist.

Background: There are numerous guidelines developed for bone health. Yet, it is unclear whether the differences in guideline development methods explain the variability in the recommendations for vitamin D and calcium intake. The objective of this systematic review was to collate and compare recommendations for vitamin D and calcium across bone health guidelines, assess the methods used to form the recommendations, and explore which methodological factors were associated with these guideline recommendations. Methods: We searched MEDLINE, EMBASE, CINAHL, and other databases indexing guidelines to identify records in English between 2009 and 2019. Guidelines or policy statements on bone health or osteoporosis prevention for generally healthy adults aged ≥40 years were eligible for inclusion. Two reviewers independently extracted recommendations on daily vitamin D and calcium intake, supplement use, serum 25 hydroxyvitamin D [25(OH)D] level, and sunlight exposure; assessed guideline development methods against 25 recommended criteria in the World Health Organization (WHO) handbook for guideline development; and, identified types identified types of evidence underpinning the recommendations. Results: we included 47 eligible guidelines from 733 records: 74% of the guidelines provided vitamin D (200~600–4000 IU/day) and 70% provided calcium (600–1200 mg/day) recommendations, 96% and 88% recommended vitamin D and calcium supplements, respectively, and 70% recommended a specific 25(OH)D concentration. On average, each guideline met 10 (95% CI: 9–12) of the total of 25 methodological criteria for guideline development recommended by the WHO Handbook. There was uncertainty in the association between the methodological criteria and the proportion of guidelines that provided recommendations on daily vitamin D or calcium. Various types of evidence, including previous bone guidelines, nutrient reference reports, systematic reviews, observational studies, and perspectives/editorials were used to underpin the recommendations. Conclusions: There is considerable variability in vitamin D and calcium recommendations and in guideline development methods in bone health guidelines. Effort is required to strengthen the methodological rigor of guideline development and utilize the best available evidence to underpin nutrition recommendations in evidence-based guidelines on bone health.

The United Kingdom was among the first countries to introduce a salt reduction program in 2003 to reduce cardiovascular disease (CVD) incidence risk. Despite its initial success, the program has stalled recently and is yet to achieve national and international targets. We used age- and sex-stratified salt intake of 19 to 64 years old participants in the National Diet and Nutrition Surveys 2000 to 2018 and a multistate life table model to assess the effects of the voluntary dietary salt reduction program on premature CVD, quality-adjusted survival, and health care and social care costs in England. The program reduced population-level salt intake from 9.38 grams/day per adult (SE, 0.16) in 2000 to 8.38 grams/day per adult (SE, 0.17) in 2018. Compared with a scenario of persistent 2000 levels, assuming that the population-level salt intake is maintained at 2018 values, by 2050, the program is projected to avoid 83 140 (95% CI, 73 710–84 520) premature ischemic heart disease (IHD) cases and 110 730 (95% CI, 98 390–112 260) premature strokes, generating 542 850 (95% CI, 529 020–556 850) extra quality-adjusted life-years and £1640 million (95% CI, £1570–£1660) health care cost savings for the adult population of England. We also projected the gains of achieving the World Health Organization target of 5 grams/day per adult by 2030, which by 2050 would avert further 87 870 (95% CI, 82 050–88 470) premature IHD cases, 126 010 (95% CI, 118 600–126 460) premature strokes and achieve £1260 million (95% CI, £1180–£1260) extra health care savings compared with maintaining 2018 levels. Strengthening the salt reduction program to achieve further reductions in population salt intake and CVD burden should be a high priority.

271 Background: Mutations in oncogenic KRAS have been widely accepted as the signature genomic alteration (GA) in sporadic PDAC, but therapeutic efforts aimed at targeting constitutively activated KRAS have been disappointing. We examined somatic GAs in KRAS WT PDAC utilizing a CGP platform to identify actionable targets. Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) PDAC clinical specimens and CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 unique reads. Alterations in the RAS/ RAF/ MEK pathway genes ( KRAS, NRAS, HRAS, ARF, BRAF, EGFR, MAP2K2, MAP2K1, MAPK1) and DNA Damage Repair (DDR) pathway genes ( BRCA1/2, ATM, ATR, BRIP1, RAD50, RAD51, RAD52, PALB2, CHEK1, CHEK2) were examined. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. TMB was categorized based on mutations(m)/Mbp of DNA - high (H; > 20), Intermediate (I; 8-20) and low (L; < 8). Results: CGP was performed on 3426 PDAC specimens; 1815 (53%) were male, 390 (11.3%) were KRAS WT. GAs in the RAS/ RAF/ MEK pathway were identified in 90.6% of all cases, while 68 (17.4%) KRAS WT cases had one or more GAs in RAS/ RAF/ MEK pathway genes. DDR pathway GAs were identified in 1405 (41%) cases for a total of 2050 GAs, and 180 (46%) KRAS WT cases for a total of 285 GAs. DDR pathway alterations were common in KRAS WT PDAC compared to KRAS mutated PDAC (p = 0.028). Among the 842 (24.6%) cases with available TMB data, 5 (0.6%), 104 (12.3%) and 733 (87.1%) pts had H, I and L, TMB respectively. Among 88 (22.6%) KRAS WT cases with available TMB data, 2 (2.3%), 12 (13.6%) and 74 (84.1%) pts had H, I and L, TMB, respectively. MSI status was available in 2314 (67.5%) cases, 13 (0.6%) were MSI-high (MSI-H); among the KRAS WT cases, 222 (57%) had MSI status available, 3 (1.3%) were MSI-H. Conclusions: MSI-H status and high TMB are rare in PDAC, regardless of KRAS mutation status. GAs in the DDR pathway are relatively common in PDAC and may serve as predictive biomarkers for platinum chemotherapeutic agents and/or PARP inhibitors. Prospective validation of such predictive gene signatures will improve therapeutic efficacy and minimize toxicities.

Tan lesions with dark margins containing concentric rings of black pycnidia were observed on leaves and pods of hairy tare (Vicia hirsuta L.) growing near Ateni, GA (41°54.631′N, 44°05.586′E, elev. 730 m) on 1 July 2004. Lesions were reminiscent of those induced by Ascochyta rabiei (Pass.) Labrousse on chickpea (Cicer arietinum L.). At the time of collection, necrotic lesions were observed on the stems, leaflets, and pods of several plants. The fungus was isolated by surface-disinfecting small pieces of infected tissue in 95% EtOH for 10 s, 1% NaOCl for 1 min, and then deionized H20 for 1 min. Tissue pieces were placed on 3% water agar (WA) for 24 h under fluorescent lights with a 12-h photoperiod to induce sporulation. Single-conidial isolations were made by streaking cirrhi on 3% WA and picking germinated single conidia. After 14 days of growth, the isolated fungus had colony morphology similar to that of A. rabiei on V8 juice agar. A conidial suspension of the fungus (1 × 105 conidia/ml) was spray-inoculated onto 2-week-old plants including PI lines 628303, 628304, 420171, and 422499 of V. hirsuta and C. arietinum cv. Burpee. Plants were obtained from the USDA Western Region Plant Introduction Station, Pullman, WA, and 20 replicate plants of each genotype were inoculated. Inoculated plants were covered with a plastic cup to maintain high humidity and incubated in a growth chamber for 48 h at 18°C. Following removal of the cups, characteristic Ascochyta blight lesions were apparent 14 days after inoculation on both plant species. DNA was extracted from the isolate and 610 bp of the glyceraldehyde-3-phosphate-dehydrogenase gene (G3PD), 364 bp of the chitin synthase 1 gene, and 330 bp of the translation elongation factor 1-alpha gene were amplified with gpd-1 and gpd-2 primers (1), CHS-79 and CHS-354 primers (2), and EF1-728F and EF1-986R primers (2), respectively. Amplicons were direct sequenced on both strands and a BLAST search of the NCBI nucleotide database with consensus G3PD, CHS, and EF sequences revealed the chickpea pathogen Didymella rabiei (anamorph Ascochyta rabiei) accessions DQ383958, DQ386480, and DQ386488 as the closest matches in the databases with 95, 95, and 88% sequence similarity, respectively. These results, coupled with the morphological identification and the inoculation results, confirm the identity of the fungus as Ascochyta sp. Further research needs to be performed to determine if this represents a new species of Ascochyta. The identification of this fungus is part of a larger project to develop a phylogeny for Ascochyta spp. infecting cultivated legumes and their wild relatives that will provide a framework for the study of the evolution of host specificity and speciation of plant-pathogenic fungi. This is the second report of an Ascochyta species on V. hirsuta, and to our knowledge, the first report of Ascochyta blight of this host in the Republic of Georgia. References: (1) M. L. Berbee et al. Mycologia 91:964, 1999. (2) I. Carbone and L. M. Kohn. Mycologia 91:553, 1999.

Abstract MRC UKALLXII/ECOG2993 accrued 739 ECOG pts over 13 years. ECOG’s reference laboratories centrally characterized 613 (91%) and 505 were B-Lin ALLs. Expression of 32 antigens (Ags), including 9 myeloid-associated Ags, was determined by multiparameter flow cytometry on gated blasts, both as percentage of Ag expressing blasts and intensity of antibody staining (equivalent of Ag density). To test for the potential therapeutic efficacy of monoclonal antibodies, such as rituximab, epratuzumab, alemtuzumab, or gemtuzumab in future trials, expression of Ags for these antibodies (CD20, CD22, CD52, or CD33, respectively) was determined. In E2993, 14% of pts typed as Pro-B (CD10 negative), 71% as Early Pre-B (CD10 positive), 13% as Pre-B (intracytoplasmic mu positive), and 2% as Mature B-ALL (surface mu chains positive). CD20 expression correlated with the stage of B-lymphoid maturation (p=5.4E-13) (see table). Median CD20 intensity of fluorescence was lowest in Pro-B and highest in Mature B-ALL. Membrane expression of CD22 was lower in Pro-B compared with the other three groups, Early Pre-B, Pre-B and Mature B (p=1.0E-5) but indistinguishable among the latter three (p=0.21). While levels of CD20 and CD22 had no effect on complete remission (CR) and overall survival (OS) univariatly, higher CD22 expression was significantly correlated with better OS (p=0.02) in a bivariate Cox model of CD20 and CD22. With respect to myeloid Ags, CD33/CD13 expression was associated with Early Pre-B (p=0.02), and CD65(s)/CD15(s) with Pro-B ALL (p<0.0001). While CD65(s) and CD15(s) did not affect outcome, the combined expression of CD33/ CD13 conferred an inferior prognosis; this effect was due to the association of CD33/ CD13 with BCR/ABL positivity (p<0.0001). BCR/ABL negative B-Lin ALL (N=350) expressed CD33 on a median of only 4% of blasts, compared with a median of 54% in BCR/ABL positive ALL (N=152) (p=3.5E-09). However, intensity of CD33 staining was significantly lower in both BCR/ABL negative and positive blasts (median 3.1) compared with leukemic myeloblasts (median 56) (p=<0.001). Median CD52 expression was higher in BCR/ABL positive versus negative B-Lin ALL (p=3.5E-06); in neither group was CD52 associated with outcome. We conclude that antibodies to CD52 are better suited for BCR/ ABL positive than negative B-Lin ALL. Since expression of CD33 in ALL is weak, CD33- independent effects of gemtuzumab must be investigated. Low CD20 combined with high CD22 expression confers superior OS. The expression of these Ags in most B-Lin ALL pts justifies the incorporation of antibodies into frontline chemotherapy regimens. B-Lin ALL Stage CD20 Percentage Median Intensity CD22 Percentage Median Intensity ≥20% ≥50% ≥75% ≥20% ≥50% ≥75% Pro-B 21 10 3 2 88 72 55 12 Early PreB 66 48 37 21 96 90 84 28 Pre-B 61 46 37 21 100 90 81 37 Mature B 87 80 64 106 92 84 80 9

Background:Eosinophilic granulomatosis with polyangiitis (EGPA) is a relapsing disease with frequent glucocorticoid (GC) dependence. Mepolizumab (MEPO) has been demonstrated to reduce flares and spare GC. However, EGPA is a heterogeneous disease and the effects of MEPO on specific disease manifestations has not been completely delimitated.Objectives:To analyze the impact of MEPO on manifestations derived from small-vessel vasculitis, ENT symptoms, asthma, eosinophilic tissue infiltration and ANCA status in a single-centre cohort of EGPA patients.Methods:Medical chart of EGPA patients treated with MEPO were reviewed to describe demographics, clinical characteristics, steroid dose at the initiation of MEPO and during follow-up, flares, disease activity, damage accrual and laboratory results.Results:Among 52 EGPA patients regularly controlled in our department, 11 patients were treated with MEPO. MEPO was prescribed when a) patients required prednisone (PDN) at ≥ 7.5 mg/d to maintain stability, or b) when maintained with < 7.5mg/d, presented at least 4 exacerbations/year requiring an increase in PDN dose. 6 were males and 5 females, with a mean age of 54 years at MEPO initiation. Baseline characteristics of the patients and course under treatment are presented in Table 1. ENT involvement, followed by asthma and eosinophil-related tissue-infiltration (ETI) were the most common symptoms when prescribing MEPO. Regarding treatment, patients received MEPO at 100-300mg SC monthly. The definition of flare was the same used in the MIRRA trial1. The mean time of treatment with MEPO was 34 months. All patients achieved a BVAS score of 0 points at 12 months or earlier. In general, patients reduced the number of flares, which tended to be milder, and all related to asthma or ENT manifestations. All improved their asthma control, but 3 of them persisted with recurrent ENT symptoms in spite of treatment with MEPO. None of them had vasculitic manifestations (cutaneous, neurological, gastrointestinal, renal) manifestations during treatment. All patients were able to tapper their PDN dose to ≤5 mg/day or less, except 3 patients. Of the 3 patients who required ≥5mg/d, 1 had severe asthma, but diminished the previous PDN dose (22.5 mg/d pre-MEPO, 10 mg/d currently) and the yearly rate of flares (8.2 pre-MEPO, 0.64 under-MEPO). The other one notably improved his asthma, but had ENT symptoms that responded unsatisfactorily to MEPO and required a maintenance PDN dose of 7.5 mg/d. The last one, improved her asthma control and was able to begin PDN tapering, but persisted with ENT symptoms. Regarding damage accrual, 6 patients remained stable during treatment, and 5 worsened. Two of three ANCA positive patients remained positive in spite of treatment.Table 1.Baseline characteristics at diagnosisAt mepolizumab initiationAfter mepolizumab (last follow-up)Age, median (range) years49 (23-67)54 (35-69)-Male/Female, n (%)6/5 (54.5%/45.5%)--BVAS, median (range)11 (2-20)2 (0-6)0FFS, value (n, %)1 (1, 9.1%)--VDI, mean (range)-1.7 (0-5)2.3 (0-5)Asthma, n (%)11 (100%)3 (27.3%)0 (0%)ENT, n (%)10 (90%)4 (36.4%)3 (27.3%)SVV, n (%)4 (36.4%)0 (0%)0 (0%)ETI signs/symptoms, n (%)7 (63.6%)2 (18.2%)0 (0%)Constitutional symptoms, n (%)4 (36.4%)0 (0%)0 (0%)Eosinophils, mean (range) cells x1095500 (600-8850)240 (0-600)55 (0-200)ANCA positivity (IIF)7 (77.8%)32Anti-MPO titers, mean (range)286 (93-740)88 (3-739)7 (3-37)Yearly rate of flares-1,750.51Immunosuppressants, n-31Prednisone dose, mg/d (range)8 (7.5-25)11.4 (5-22.5)5.125 (0-10)Conclusion:MEPO was effective for the treatment of patients with EGPA, with a reduction in the number and severity of flares and a decrease in PDN doses. A worse response of ENT involvement was observed. No vasculitic flares were observed in spite of GC reduction. Mepolizumab did not prevent damage accrual during the treatment period.References:[1]Wechsler ME et al. MEPO or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med. 2017.Acknowledgements:Funding: Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 (PI18/00461), co-funded by Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER) and by Río Hortega program (ISCIII, CM19/00032).Disclosure of Interests:Roberto Ríos-Garcés: None declared, Sergio Prieto-González: None declared, José Hernández-Rodríguez: None declared, Maria C. Cid Paid instructor for: GSK and Vifor, Consultant of: GSK, Abbvie and Janssen, Grant/research support from: Kiniksa and Roche, Georgina Espígol-Frigolé Consultant of: Janssen, Grant/research support from: Roche

Nickel (Ni) laterites are regolith materials derived from ultramafic rocks and play an important role in the world's Ni production. Ni-laterite deposits are the supergene enrichment of Ni formed from the intense chemical and mechanical weathering of ultramafic parental rocks. In Vietnam, the weathering profile containing Ni laterite was first discovered in the Ha Tri massive (Cao Bang). This profile develops on the Ha Tri serpentinized peridotite rocks classified to the Cao Bang mafic-ultramafic complex (North Vietnam) and exhibits thick weathered zone (10 - 15m). This work carried out a detailed study of the weathering profile at the center of Ha Tri massive. Samples from different horizons of the profile were collected and analyzed in detail by XRF, XRD and SEM-EDX methods to establish the relationship between the Ni-rich supergene products and the parental peridotites (lherzolite) rocks in Ha Tri massive. The results show that the saprolite horizon is most Ni-rich in the weathering profile in Ha Tri. In this horizon, Ni-silicate minerals of garnierite group such as pimelite, nepouite and other Mg-Ni silicates have been found. The appearance of minerals of garnierite group is due to the exchange of Mg by Ni during weathering of peridotite minerals, especially olivine, which leads to the enrichment of the supergene Ni. The occurrence of Ni silicates suggests the existence of the supergene Ni ore in the weathering profile of the Ha Tri massive.References Bosio N.J., Hurst J.V., Smith R.L., 1975. Nickelliferousnontronite, a 15 Å garnierite, at Niquelandia, Goias Brazil. Clays Clay Miner., 23, 400-403. Brand N.W., Butt C.R.M., Elias M., 1998. Nickel Laterites: Classification and features. AGSO Journal of Australian Geology & Geophysics, 17(4), 81-88. Bricker O.P., Nesbitt H.W. and Gunter W.D., 1973. The stability of talc. American Mineralogist, 58, 64-72. Brindley G.W. and Hang P.T., 1973. 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Lateritic weathering of pyroxenites at Niquelandia, Goais, Brazil: The supergene behavior ofnickel: Economic Geology, 85, 1010-1023. Das S.K., Sahoo R.K., Muralidhar J., Nayak B.K., 1999. Mineralogy and geochemistry of profilesthrough lateritic nickel deposits at Kansa,Sukinda, Orissa. Joural of Geoogical. SocietyIndia, 53, 649-668. Decarreau A., Colin F., Herbillon A., Manceau A., Nahon D., Paquet H., Trauth-Badaud D.,Trescases J.J., 1987. Domain segregation in NiFe-Mg-Smectites. Clay Minerals, 35, 1-10. Freyssinet P., Butt C.R.M. and Morris R.C., 2005. Oreforming processes related to lateritic weathering. Economic Geology, 100th aniversary volume, 681-722.Garnier J., Quantin C., Martins E.S., Becquer T., 2006. Solid speciation and availability of chromium in ultramafic soils from Niquelandia, Brazil. Journal of Geochemical Exploration, 88, 206-209. Garnier J., Quantin C., Guimarães E., Becquer T., 2008. Can chromite weathering be a source of Cr in soils? Mineralogy Magazine, 72, 49-53. Gleeson S.A., Butt C.R. and Elias M., 2003. Nickel laterites: A review. SEG Newsletter, 54, 11-18. Gleeson S.A., Butt C.R., Wlias M., 2003. Nickellaterites: a review. SEG Newsletter, Society of Economic Geology, 54. Available from www.segweb.org. Golightly J.P., 1981. Nickeliferous laterite deposits. Economic Geology, 75th Anniversary volume, 710-735. Golightly J.P., 2010. Progress in understanding the evolution of nickel laterite. Society of Economic Geology, In Special Publication, 15, 451-485. Manceau A. and Calas G., 1985. Heterogeneous distribution of nickel in hydrous silicates from New Caledonia ore deposits. American Mineralogist, 70, 549-558. Nguyen Van Pho, 2013. Tropic weathering in Vietnam (in Vietnamese). Pubisher Science and Technology, 365p.Ngo Xuan Thanh, Tran Thanh Hai, Nguyen Hoang, Vu Quang Lan, S. Kwon, Tetsumaru Itaya, M. Santosh, 2014. Backarc mafic-ultramafic magmatism in Northeastern Vietnam and its regional tectonic significance. Journal of Asian Earth Sciences, 90, 45-60.Pelletier B., 1983. Localisation du nickel dans les minerais ‘‘garnieritiques’’ de Nouvelle-Caledonie. Sciences Ge´ologique: Me´moires, 73, 173-183.Pelletier B., 1996. Serpentines in nickel silicate ores from New Caledonia. In Grimsey E.J., and Neuss I. (eds): Nickel ’96, Australasian Institute of Miningand Metallurgy, Melbourne, Publication Series 6(9), 197-205. Proenza J.A., Lewis J.F., Galı´ S., Tauler E., Labrador M., Melgarejo J.C., Longo F. and Bloise G., 2008. Garnierite mineralization from Falcondo Ni-laterite deposit (Dominican Republic). Macla, 9, 197-198. Soler J.M., Cama J., Galı´ S., Mele´ndez W., Ramı´rez, A., andEstanga, J., 2008. Composition and dissolution kinetics ofgarnierite from the Loma de Hierro Ni-laterite deposit,Venezuela. Chemical Geology, 249, 191-202. Springer G., 1974. Compositional and structural variations ingarnierites. The Canadian Mineralogist, 12, 381-388. Springer G., 1976. Falcondoite, nickel analogue of sepiolite. The Canadian Mineralogist, 14, 407-409.Svetlitskaya T.V., Tolstykh N.D., Izokh A.E., Phuong Ngo Thi, 2015. PGE geochemical constraints on the origin of the Ni-Cu-PGE sulfide mineralization in the Suoi Cun intrusion, Cao Bang province, Northeastern Vietnam. Miner Petrol, 109, 161-180.Tran Trong Hoa, Izokh A.E., Polyakov G.V., Borisenko A.S., Tran Tuan Anh, Balykin P.A., Ngo Thi Phuong, Rudnev S.N., Vu Van Van, Bui An Nien, 2008. Permo-Triassic magmatism and metallogeny of Northern Vietnam in relation to the Emeishan plume. Russ. Geol. Geophys., 49, 480-491.Trescases J.J., 1975. L'évolution supergene des roches ultrabasiques en zone tropicale: Formation de gisements nikelifères de Nouvelle Caledonie. Editions ORSTOM, Paris, 259p.Tri T.V., Khuc V. (eds), 2011. Geology and Earth Resources of Vietnam. Publishing House for Science and Technology, 645p (in English). Villanova-de-Benavent C., Proenza J.A., GalíS., Tauler E., Lewis J.F. and Longo F., 2011. Talc- and serpentine-like ‘‘garnierites’’ in the Falcondo Ni-laterite deposit, Dominican Republic. ‘Let’s talk ore deposits’, 11th Biennial Meeting SGA 2011, Antofagasta, Chile, 3p.Wells M.A., 2003. Goronickel laterite deposit. New Caledonia. CRC LEME, p.3.

Background: Romiplostim, a thrombopoietin (TPO) receptor agonist approved for children and adults with chronic ITP, was evaluated in children with ITP in a ≤3-year open-label trial. Interim results were previously reported (Grainger et al., Blood 2017 130:2334). Here we present updated results as of 27 Mar 2019. Methods: Eligible children from 17 countries with ITP for ≥6 months and screening platelet count ≤30×109/L (or uncontrolled bleeding) received SC romiplostim (1 μg/kg titrated to 10 μg/kg to maintain platelet counts of 50-200×109/L). In Europe, bone marrow was evaluated at baseline and after 1 (day 365 ± 4 weeks) or 2 (day 730 ± 4 weeks) years. The primary endpoint was % time with a platelet response (platelet count ≥50×109/L, no rescue therapy in preceding 4 weeks) in months 0-6. Results: A total of 203 patients (pts) received ≥1 dose; the median (interquartile range [IQR]) age was 10 (6-13) and median (IQR) platelet count 14 (7-23.5×109/L). The median (IQR) duration of treatment was 145 (39-156) weeks, median (IQR) % of time with a platelet response in months 0-6 was 50% (17-83%), with 88% (179/203) of pts having a platelet response at least once (Fig. 1A). In all pts, the median (IQR) % of time with an increase in platelet counts ≥20×109/L above baseline from week 2 until the end of treatment was 79% (39-92%). Median and lower quartile platelet counts were both consistently >50×109/L from week 12 and 48, respectively, and did not vary by age. Eleven pts maintained platelet counts ≥50×109/L without ITP medications (including romiplostim) for ≥24 weeks; median (IQR) time to onset was 50 (24-80) weeks after starting romiplostim. During the study, 60 (30%) pts received rescue therapy, typically within weeks 1-36, and 3 underwent splenectomy. With a total exposure of 428.7 patient-years, median (IQR) average weekly romiplostim dose over the entire study was 6.9 (4.6-8.9) µg/kg; 8.5 (5.0-10.0) μg/kg at 1 year (n=144) and 6.0 (3.0-10.0) μg/kg at 2 years (n=129; Fig. 1B). Self-administration was initiated in 68% of pts. Ninety-five pts (46.8%) discontinued treatment: reasons included lack of efficacy (n=43 [21.2%]), patient request (n=15 [7.4%]), adverse event (AE; n=9 [4.4%]), and neutralizing antibodies (NAb; n=7 [3.4%]). AEs occurred in 192 pts (94.6%); the most frequent were epistaxis (38.4%), headache (37.9%), and nasopharyngitis (36.9%). Serious AEs (SAEs) occurred in 59 (29.1%) pts, including epistaxis (5.9%), decreased platelet count (4.4%), and thrombocytopenia and NAb (2% each); 8 pts had treatment-related SAEs (NAbs [n=4], headache and abdominal pain [each n=2], and presyncope [n=1]). Bleeding occurred in 69% of pts over the study, decreasing over time, with bleeding in 18% of pts from week 144 to the end of treatment. Bleeding-related AEs occurring in >10% of pts were epistaxis (38.4%), petechiae (23.6%), hematoma (20.7%), contusion (19.2%) and gingival bleeding (10.3%). CTCAE grade ≥3 bleeding events occurred in 20 pts (9.9%) and included epistaxis (n=9 [4.4%]), and persistent ITP (n=3 [1.5%]). In pts with no evidence of NAbs at baseline, there were 7 cases of NAbs to romiplostim (2 were transient) and 1 transient NAbs to TPO; only 1 pt, with NAbs to romiplostim, had a reduced therapeutic effect. Of 75 European pts with evaluable baseline bone marrow biopsies [modified Bauermeister scores: grade 0 (no reticulin, n=16), 1 (fine fibers, n=54), or 2 (fine fiber network, n=5)], 27 had evaluable on-study biopsies after 1 year and 36 after 2 years (Table). Of these, 5 pts developed increased reticulin at year 1 and 17 at year 2. One pt had an increase in modified Bauermeister score from baseline of ≥2 grades (increase from grade 0 to 2), 4 pts had an increase in 1 grade, 1 a decrease in 2 grades, and 3 a decrease in 1 grade in year 1. In year 2, 15 pts had an increase in 1 grade and 3 pts a decrease in 1 grade. No pts developed collagen and no bone marrow abnormalities were detected. Conclusion: Over the course of the study with >30 months of treatment, on a median dose of 6.9 μg/kg, 88% of children had a platelet response, median platelet counts were ≥20×109/L above baseline 79% of the time and >50×109/L from week 12. An important new safety signal over 429 patient-years was the 3.4% of NAbs to romiplostim; children develop NAbs with romiplostim more frequently than adults. Bone marrow findings showed that children, like adults, did not develop clinically important fibrosis. Disclosures Grainger: Amgen: Consultancy, Speakers Bureau; Ono: Consultancy; Alexion: Consultancy; ITP Support Association: Other: medical advisor; Octapharma: Consultancy; Biotest: Consultancy; Novartis: Consultancy, Speakers Bureau. Bussel:Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Physician Education Resource: Speakers Bureau; 3S Bio: Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Tarantino:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator initiated study, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment; Pfizer: Other: PI for program grant; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial PI; Grifols: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cooper:Novartis: Honoraria, Other: clinical trial; Principia: Honoraria, Other: clinical trial; UCB: Other: clinical trial; Rigel: Honoraria, Other: clinical trial; Amgen: Honoraria, Other: clinical trial. Despotovic:Novartis: Research Funding; Dova: Honoraria. Wang:Amgen: Employment. Eisen:Amgen: Employment, Other: stock ownership. Bowers:Amgen: Employment, Other: stock ownership.

Abstract BACKGROUND Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated reductions in splenomegaly and disease-related symptoms, as well as improved survival, in patients with MF and has proved superior to placebo and best available therapy in the 2 phase 3 COMFORT studies. JUMP (JAK Inhibitor Ruxolitinib in Myelofibrosis Patients) is a phase 3b, expanded-access trial for countries with no access to ruxolitinib outside a clinical trial and was designed to assess the safety and efficacy of ruxolitinib in patients with MF. As of 03 June 2014, 2027 patients have been enrolled in 25 countries, with a planned enrollment of 2500 patients. METHODS Eligible patients had MF classified as high risk, intermediate (Int)-2 risk, or Int-1 risk, with a palpable spleen (≥ 5 cm from the costal margin). Patients received starting doses of ruxolitinib based on platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to < 100 × 109/L], 15 mg bid [100 to 200 × 109/L], or 20 mg bid [> 200 × 109/L]). The primary endpoint was assessment of safety and tolerability of ruxolitinib. Additional analyses included changes in palpable spleen length and symptom scores as measured by the FACT-Lymphoma Total Score (FACT-Lym TS). The final analysis will be performed after all patients have completed 24 months of treatment or ended treatment due to commercial availability. RESULTS This analysis includes results for 1144 enrolled patients (primary MF, 58.8%; n = 673) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2014). At baseline, median age was 68 y (range, 18-89 y); 46.7% were female; median palpable spleen length was 13 cm below the costal margin; median hemoglobin was 105 g/L (range, 44-200 g/L) and 40.3% of patients had hemoglobin levels ˂ 100 g/L; median platelet level was 256 × 109/L (75-1910 × 109/L); mean FACT-Lym TS was 41.9. Most patients (69%) remained on treatment (35.5%) or completed treatment per protocol (33.5%; transition to commercial drug). Primary reasons for discontinuation included adverse events (AEs; 13.8%), disease progression (7.1%), and death (3.8%). Median exposure was 11.1 months; the median average daily dose was 37.2 mg for patients starting at 20 mg bid (64%; n = 728) and 23.4 mg for patients starting at 15 mg bid (33%; n = 374). The majority of patients (75.7%) had dose increases/decreases and 23.9% had a dose interruption. The most common hematologic grade ≥ 3 AEs were anemia (33.0%), thrombocytopenia (12.5%), and neutropenia (3.9%), which led to discontinuation in 2.6%, 3.2%, and 0.3% of patients, respectively. Mean hemoglobin levels declined from baseline (108 g/L) to a nadir of 85 g/L at 8 to 12 weeks and increased to near-baseline levels after week 12; mean platelet levels decreased from baseline (318 × 109/L) to a nadir of 139 × 109/L and remained stable over time. The most common nonhematologic AEs (≥ 10%) were diarrhea (14.5%), pyrexia (13.3%), fatigue (12.9%), and asthenia (12.5%) and were primarily grade 1/2; grade ≥ 3 AEs were low overall (< 2%), except pneumonia (3.6%), which led to discontinuation in 6 patients (0.5%). Serious AEs were reported for 32.3% of patients. Rates of infections were low; all-grade infections ≥ 5% included nasopharyngitis (6.3%), urinary tract infection (6.0%), and pneumonia (5.3%). Tuberculosis was reported for 3 patients (0.3%; no grade 3/4); no hepatitis B was reported. At weeks 24 and 48, 55% (431/782) and 61% (301/497) of patients achieved a ≥ 50% reduction from baseline in palpable spleen length, respectively; 23% (181/782) and 18% (88/497) had 25% to 50% reductions. Most patients (69%; 733/1062) experienced a ≥ 50% reduction in spleen length from baseline at any time (Figure). Clinically significant improvements on the FACT-Lym TS were seen as early as week 4 and were maintained at week 48 (mean change from baseline: week 4, 11.0; week 48, 9.4; the range for the minimally important difference is 6.5 to 11.2 points). CONCLUSIONS The JUMP study includes the largest cohort of MF patients treated with ruxolitinib reported to date. Consistent with previous reports, the most common AEs were anemia and thrombocytopenia; however, they rarely led to discontinuation. As observed previously, the majority of patients experienced reductions in spleen length and clinically meaningful improvements in symptoms were observed with ruxolitinib treatment. Overall, the safety and efficacy profile of ruxolitinib in JUMP is consistent with that in the phase 3 COMFORT studies. Figure 1 Figure 1. Disclosures le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Griesshammer:Shire: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; Amgen: Honoraria. Schafhausen:Novartis: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Janssen: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Tannir:Novartis: Employment. Ronco:Novartis: Employment. Ghosh:Novartis: Employment. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding.