Relative oral bioavailability of three formulations of vitamin D3: An open-label, three-treatment study

Background: Supplementation of vitamin D2 or vitamin D3 is recommended for vitamin D deficiency. Weekly supplementation of 60,000 IU of vitamin D3 increases serum 25(OH) D to optimal values. Various marketed forms of vitamin D3 include tablets, capsule, granules and oral solution. The main objective of this study is to compare the relative bioavailability of vitamin D3 oral solution with vitamin D3 tablet and capsule.Methods: This is an open-label, randomized, single-dose, three-treatment study to compare the relative bioavailability of vitamin D3 oral solution with capsule and tablet. Subjects (n=70) were supplemented with single dose of one of these formulations and their blood sample were assessed for Cmax, AUC0-28d and Tmax.Results: The logarithmic transformed data of pharmacokinetic parameters were analyzed for 90% Confidence Intervals (CI) using ANOVA. The mean (90% CI) values of vitamin D3 oral solution against tablet for the ratio of Cmax and AUC0-28d were 113.00 (105.32-121.23) and 105.54 (97.95-113.72) respectively. The mean (90% CI) values of vitamin D3 oral solution against capsule for the ratio of Cmax and AUC0-28d were 115.02 (106.38 - 124.37) and 112.33 (104.44 - 120.81) respectively. These values were within the bioequivalence range of 80-125%.Conclusions: It is concluded that vitamin D3 Oral Solution formulated with nanotechnology is bioequivalent to vitamin D3 tablet and capsule. However, oral solution of vitamin D3 shows higher Cmax and AUC when compared to tablet and capsule formulations

Effect of varying concentrations of salinity on some biochemical parameters involved in nitrogen metabolism of four grass species

ABSTRACT: Salinity adversely affects crop productivity and the quality of yield. The present work was carried out to estimate the changes in nitrogen metabolism under the influence of NaCl salinity in four selected grasses. All the species recorded a decrease in nitrate nitrogen content at the highest concentration of salinity stress (300 mM). Its maximum increase was 14 and 19% (100 mM) for Cymbopogon nardus and Cynodon dactylon, respectively. The maximum increase in nitrite nitrogen found was 11% (200 mM) in Cymbopogon nardus, 12% (100 mM) in Cynodon dactylon. The concentration of proline and amides in the leaves of all the experimental grasses showed a positive correlation with increasing concentrations of salinity. The maximum increase in proline content was 81, 88, 126, and 68% in Cymbopogon nardus, Cynodon dactylon, Pennisetum alopecuroides, and Vetiveria zizanioides, respectively, at 300 mM NaCl salinity. The concentration of free amino acids in the leaves of all the experimental grasses was considerably increased under saline condition and showed a positive correlation with increasing concentrations of salinity. Similar results were obtained in the case of amides. The concentration of nitrate reductase enzyme was elevated in Cymbopogon nardus and Pennisetum alopecuroides at lower salinity regime

TranAir: A full-potential, solution-adaptive, rectangular grid code for predicting subsonic, transonic, and supersonic flows about arbitrary configurations. User's manual

The TranAir computer program calculates transonic flow about arbitrary configurations at subsonic, transonic, and supersonic freestream Mach numbers. TranAir solves the nonlinear full potential equations subject to a variety of boundary conditions modeling wakes, inlets, exhausts, porous walls, and impermeable surfaces. Regions with different total temperature and pressure can be represented. The user's manual describes how to run the TranAir program and its graphical support programs

Breakup of 42 MeV <SUP>7</SUP>Li projectiles in the fields of <SUP>12</SUP>C and <SUP>197</SUP>Au nuclei

Inclusive cross sections of a particles and tritons from the breakup of 42 MeV 7Li by 12C and 197Au targets are presented and analysed in the framework of the Serber model. Spectral distortions due to the targets and relevant reaction mechanisms are discussed

AB0370 UTILITY OF CRP AND ESR IN THE DIAGNOSIS OF GIANT CELL ARTERITIS RELAPSE IN A PHASE 2 TRIAL OF MAVRILIMUMAB

Background:No universally accepted definition of flare currently exists in giant cell arteritis (GCA). Although relapses are defined mostly on clinical grounds (recurrence of GCA-related signs/symptoms), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) help clinicians assess disease activity. In fact, >70% of patients on glucocorticoids (GCs) alone have increased CRP or ESR when the disease is active. In contrast, tocilizumab, given its IL-6-blockade effect in the liver, rapidly reduces CRP and ESR levels, rendering them unreliable for disease activity monitoring. Mavrilimumab – a GM-CSF receptor α inhibitor with demonstrated efficacy in a Phase 2 GCA trial1 – downregulates inflammation upstream of IL-6. We hypothesized that mavrilimumab would not interfere with the utility of CRP and ESR in monitoring disease activity and in identifying GCA relapse.Objectives:To analyze the relationship between CRP/ESR and clinical disease activity in GCA patients treated with mavrilimumab.Methods:New-onset and relapsing GCA patients with active disease were recruited. GC-induced remission (no GCA symptoms and CRP <1 mg/dL or ESR <20 mm/hr) was required by baseline. Patients were randomized 3:2 to mavrilimumab 150 mg or placebo subcutaneously every 2 weeks plus a protocol-defined 26-week prednisone taper. The primary efficacy endpoint was time to relapse by Week 26. Relapse (adjudicated) was defined as recurrent GCA-related signs/symptoms, including new/worsening vasculitis on imaging, concurrent with CRP ≥1 mg/dL and/or ESR ≥30 mm/hr. CRP and ESR were also measured periodically during the trial.This post hoc analysis assessed the association of recurrent GCA-related signs/symptoms with concurrent CRP or ESR elevation post-randomization by treatment arm. We also assessed the proportion of patients with CRP or ESR elevation without GCA-related signs/symptoms up to Week 26.Results:Seventy patients were enrolled (mavrilimumab, N=42; placebo, N=28). The association of CRP or ESR elevation with unequivocal GCA-related signs/symptoms post-randomization was consistent regardless of treatment arm: 8/8 in the mavrilimumab group and 13/13 in the placebo group (Table 1). During relapse, median (range) CRP was 1.8 (1.4 – 8.4) mg/dL (mavrilimumab group) and 1.8 (1.1 – 9.0) mg/dL (placebo group). Corresponding ESR values were 39.5 (30 – 102) mm/hr (mavrilimumab group) and 49 (31 – 101) mm/hr (placebo group). Four mavrilimumab recipients had self-limited, equivocal GCA-related signs/symptoms without concurrent CRP or ESR elevation; all 4 completed the prespecified GC taper by Week 26 without need for rescue GCs, so relapse was not confirmed. At least 1 elevated CRP or ESR value in the absence of GCA-related signs/symptoms was observed in 58.8% of mavrilimumab recipients and 93.3% of placebo recipients by Week 26.Conclusion:The observed association of CRP or ESR elevation with GCA-related signs/symptoms is consistent with the upstream mechanism and supports the utility of the stringent protocol definition of relapse. The frequency and magnitude of CRP and ESR elevations at relapse were similar in both treatment groups, suggesting that CRP and ESR remain useful in assessments of disease activity in mavrilimumab-treated patients. CRP and ESR elevations without GCA-related signs/symptoms occurred more often in placebo recipients.References:[1]Cid, Unizony et al. Arthritis Rheumatol. 2020; 72 (suppl 10)Table 1.CRP and ESR levels in patients with or without GCA relapseAssessment§MavrilimumabPlaceboMavrilimumabPlaceboN=42N=28N=42N=28With RelapseWithout Relapse# of patients8 (19.1)13 (46.4)34 (81.0)15 (53.6) Elevated CRP* or ESR†8 (100.0)13 (100.0)20 (58.8)14 (93.3)  Elevated CRP*7 (87.5)10 (76.9)10 (29.4)11 (73.3)   Median (range) mg/dL1.8 (1.4 - 8.4)1.8 (1.1 - 9.0)2.6 (1.3 – 7.0)2.0 (1.0 – 6.6) Elevated ESR†6 (75.0)9 (69.2)16 (47.1)10 (66.7)  Median (range) mm/hr39.5 (30 - 102)49.0 (31 - 101)41.5 (30 - 110)53.5 (30 - 82)§# (%), except where indicated otherwise.*CRP ≥ 1 mg/dL†ESR ≥ 30 mm/hrDisclosure of Interests:Sebastian Unizony Consultant of: Janssen and Kiniksa, Grant/research support from: Genentech, Maria C. Cid Speakers bureau: Roche and Kiniksa, Paid instructor for: GSK and Vifor, Consultant of: Janssen, GSK, and Abbvie, Grant/research support from: Kiniksa, Elisabeth Brouwer Speakers bureau: Dr. E.Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017 2018 which were paid to the UMCG., Consultant of: Dr. E.Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017 2018 which were paid to the UMCG., Lorenzo Dagna Speakers bureau: Abbvie, Amgen, Biogen, BMS, Celltrion, Galapagos, Glaxo SmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Galapagos, Glaxo SmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI; clinical trial for Kiniksa, Grant/research support from: Abbvie, Amgen, BMS, Celltrion, Galapagos, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI, Merk Sharp &Dohme, Janssen, Kiniksa, Bhaskar Dasgupta Paid instructor for: Educational grant symposium/workshop for Roche-chugai, Sanofi, and Abbvie, Consultant of: CI UK for the Kiniksa trial, Grant/research support from: Educational grant symposium/workshop for Roche-chugai, Sanofi, and Abbvie, Bernhard Hellmich Consultant of: Honoraria paid to the institution for participation in the clinical trial, Eamonn Molloy: None declared, Carlo Salvarani: None declared, Bruce C. Trapnell Consultant of: Consultant member of DSMB for Kiniksa., Kenneth J Warrington Consultant of: Clinical trial support from Eli Lilly and Kiniksa, Ian Wicks: None declared, Manoj Samant Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Teresa Zhou Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Lara Pupim Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, John F. Paolini Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceutical

Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial

OBJECTIVES: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission. METHODS: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia). Active disease within 6 weeks of baseline was required for inclusion. Patients in glucocorticoid-induced remission were randomly assigned (3:2 ratio) to mavrilimumab 150 mg or placebo injected subcutaneously every 2 weeks. Both groups received a 26-week prednisone taper. The primary outcome was time to adjudicated flare by week 26. A prespecified secondary efficacy outcome was sustained remission at week 26 by Kaplan-Meier estimation. Safety was also assessed. RESULTS: Of 42 mavrilimumab recipients, flare occurred in 19% (n=8). Of 28 placebo recipients, flare occurred in 46% (n=13). Median time to flare (primary outcome) was 25.1 weeks in the placebo group, but the median was not reached in the mavrilimumab group (HR 0.38; 95% CI 0.15 to 0.92; p=0.026). Sustained remission at week 26 was 83% for mavrilimumab and 50% for placebo recipients (p=0.0038). Adverse events occurred in 78.6% (n=33) of mavrilimumab and 89.3% (n=25) of placebo recipients. No deaths or vision loss occurred in either group. CONCLUSIONS: Mavrilimumab plus 26 weeks of prednisone was superior to placebo plus 26 weeks of prednisone for time to flare by week 26 and sustained remission in patients with giant cell arteritis. Longer treatment is needed to determine response durability and quantify the glucocorticoid-sparing potential of mavrilimumab. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT03827018, Europe (EUdraCT number: 2018-001003-36), and Australia (CT-2018-CTN-01 865-1)

Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background

The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability

Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

X-ray magnetic circular dichroism study of epitaxial magnetite ultrathin film on MgO(100)

The spin and orbital magnetic moments of the Fe3O4 epitaxial ultrathin film synthesized by plasma assisted simultaneous oxidization on MgO(100) have been studied with X-ray magnetic circular dichroism (XMCD). The ultrathin film retains a rather large total magnetic moment, i.e. (2.7+-0.15) uB/f.u., which is ~ 70% of that for the bulk-like Fe3O4. A significant unquenched orbital moment up to (0.54+-0.05) uB/f.u. was observed, which could come from the symmetry breaking at the Fe3O4/MgO interface. Such sizable orbital moment will add capacities to the Fe3O4-based spintronics devices in the magnetization reversal by the electric field

Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma.

Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors