ALBERT

Description: 〈div data-abstract-type="normal"〉 〈p〉Agmantinite, ideally Ag〈span〉2〈/span〉MnSnS〈span〉4〈/span〉, is a new mineral from the Uchucchacua polymetallic deposit, Oyon district, Catajambo, Lima Department, Peru. It occurs as orange–red crystals up to 100 μm across. Agmantinite is translucent with adamantine lustre and possesses a red streak. It is brittle. Neither fracture nor cleavage were observed. Based on the empirical formula the calculated density is 4.574 g/cm〈span〉3〈/span〉. On the basis of chemically similar compounds the Mohs hardness is estimated at between 2 to 2½. In plane-polarised light agmantinite is white with red internal reflections. It is weakly bireflectant with no observable pleochroism with red internal reflections. Between crossed polars, agmantinite is weakly anisotropic with reddish brown to greenish grey rotation tints. The reflectances (〈span〉R〈/span〉〈span〉min〈/span〉 and 〈span〉R〈/span〉〈span〉max〈/span〉) for the four standard wavelengths are: 19.7 and 22.0 (470 nm); 20.5 and 23.2 (546 nm); 21.7 and 2.49 (589 nm); and 20.6 and 23.6 (650 nm), respectively.〈/p〉 〈p〉Agmantinite is orthorhombic, space group 〈span〉P〈/span〉2〈span〉1〈/span〉〈span〉nm〈/span〉, with unit-cell parameters: 〈span〉a〈/span〉 = 6.632(2), 〈span〉b〈/span〉 = 6.922(2), 〈span〉c〈/span〉 = 8.156(2) Å, 〈span〉V〈/span〉 = 374.41(17) Å〈span〉3〈/span〉, 〈span〉a〈/span〉:〈span〉b〈/span〉:〈span〉c〈/span〉 0.958:1:1.178 and 〈span〉Z〈/span〉 = 2. The crystal structure was refined to 〈span〉R〈/span〉 = 0.0575 for 519 reflections with 〈span〉I 〉〈/span〉 2σ(〈span〉I〈/span〉). Agmantinite is the first known mineral of 〈span〉〈span〉〈img data-mimesubtype="gif" data-type="simple" src="http://static.cambridge.org/resource/id/urn:cambridge.org:id:binary:20190522072108342-0385:S0026461X18001391:S0026461X18001391_inline1.gif"〉 〈span data-mathjax-type="texmath"〉 〈/span〉 〈/span〉〈/span〉〈span〉M〈/span〉〈span〉II〈/span〉〈span〉M〈/span〉〈span〉IV〈/span〉S〈span〉4〈/span〉 type that is derived from wurtzite rather than sphalerite by ordered substitution of Zn, analogous to the substitution pattern for deriving stannite from sphalerite. The six strongest X-ray powder-diffraction lines derived from single-crystal X-ray diffraction data [〈span〉d〈/span〉 in Å (intensity)] are: 3.51 (s), 3.32 (w), 3.11 (vs), 2.42 (w), 2.04 (m) and 1.88 (m). The empirical formula (based on 8 apfu) is (Ag〈span〉1.94〈/span〉Cu〈span〉0.03〈/span〉)〈span〉Σ1.97〈/span〉(Mn〈span〉0.98〈/span〉Zn〈span〉0.05〈/span〉)〈span〉Σ1.03〈/span〉Sn〈span〉0.97〈/span〉S〈span〉4.03〈/span〉.The crystal structure-derived formula is Ag〈span〉2〈/span〉(Mn〈span〉0.69〈/span〉Zn〈span〉0.31〈/span〉)〈span〉Σ1.00〈/span〉SnS〈span〉4〈/span〉 and the simplified formula is Ag〈span〉2〈/span〉MnSnS〈span〉4〈/span〉.〈/p〉 〈p〉The name is for the composition and the new mineral and mineral name have been approved by the International Mineralogical Association Commission on New Minerals, Nomenclature and Classification (IMA2014-083).〈/p〉 〈/div〉

Description: 〈div data-abstract-type="normal"〉〈p〉Structural data for weishanite, an alloy of Au, Ag and Hg, were collected for the first time from a crystal from the Keystone Mine, Colorado, USA. The structure was solved in the space group 〈span〉P〈/span〉6〈span〉3〈/span〉/〈span〉mmc〈/span〉 with the unit cell 〈span〉a〈/span〉 = 2.9348(8) and 〈span〉c〈/span〉 = 4.8215(18) Å] and refined to 〈span〉R〈/span〉 = 0.0299 for 40 observed reflections [4σ(〈span〉F〈/span〉) level] and four parameters and to 〈span〉R〈/span〉 = 0.0356 for all 47 independent reflections. The weishanite structure can be considered a derivative of the zinc structure, with Au, Ag and Hg disordered in the same structural position. On this basis, we suggest that the formula is normalized to 1 atom with 〈span〉Z〈/span〉 = 2, leading, for the sample investigated, to Au〈span〉0.41〈/span〉Ag〈span〉0.31〈/span〉Hg〈span〉0.28〈/span〉 (electron microprobe data). Accordingly, weishanite can be considered the Au-rich isotype of schachnerite. A comparison with other Au/Ag-Hg alloys is presented together with a critical discussion about the nomenclature rules to be applied to alloys and simple metals.〈/p〉〈/div〉

Description: Gamma-ray bursts (GRBs) are the most luminous explosions in the Universe, yet the nature and physical properties of their energy sources are far from understood. Very important clues, however, can be inferred by studying the afterglows of these events. We present optical and X-ray observations of GRB 130831A obtained by Swift, Chandra , Skynet, Reionization And Transients Infra-Red camera, Maidanak, International Scientific Optical-Observation Network, Nordic Optical Telescope, Liverpool Telescope and Gran Telescopio Canarias. This burst shows a steep drop in the X-ray light curve at ~=10 5  s after the trigger, with a power-law decay index of α ~ 6. Such a rare behaviour cannot be explained by the standard forward shock (FS) model and indicates that the emission, up to the fast decay at 10 5  s, must be of ‘internal origin’, produced by a dissipation process within an ultrarelativistic outflow. We propose that the source of such an outflow, which must produce the X-ray flux for ~=1 d in the cosmological rest frame, is a newly born magnetar or black hole. After the drop, the faint X-ray afterglow continues with a much shallower decay. The optical emission, on the other hand, shows no break across the X-ray steep decrease, and the late-time decays of both the X-ray and optical are consistent. Using both the X-ray and optical data, we show that the emission after ~=10 5  s can be explained well by the FS model. We model our data to derive the kinetic energy of the ejecta and thus measure the efficiency of the central engine of a GRB with emission of internal origin visible for a long time. Furthermore, we break down the energy budget of this GRB into the prompt emission, the late internal dissipation, the kinetic energy of the relativistic ejecta, and compare it with the energy of the associated supernova, SN 2013 fu.

Description: Asparaginase (ASNase) is one of the cornerstones of the multi-drug treatment protocol that is used to treat acute lymphoblastic leukemia (ALL) in pediatric and adult patients. Despite the fact that ASNase has been used in ALL treatment protocols for decades, little is known about the biodistribution and the mechanism of ASNase turnover in vivo. A large inter-individual variation in ASNase pharmacokinetics is observed in patients. While elevated ASNase levels are associated with an increase in adverse events, underexposure, frequently caused by antibody mediated clearance, seriously reduces therapeutic efficacy. To date, it is not possible to predict pharmacokinetics of ASNase in individual patients and therefore current therapeutic protocols are supported by frequent monitoring of ASNase levels and adjustments of administration schemes. We used an in vivo imaging approach to study ASNase biodistribution and pharmacodynamics in a mouse model and provide in vitro and in vivo evidence that identifies the endo-lysosomal protease Cathepsin B in macrophages as a critical component of ASNase degradation. Results/Discussion Mice were injected with 111Indium-labeled ASNase and biodistribution was monitored by quantitative microSPECT/CT scans and ex vivo analysis of organs using a gamma counter. Over time, ASNase accumulated in the liver and particularly the spleen and the bone marrow. We hypothesized that macrophages in these organs, efficiently take up the ASNase, thereby rapidly clearing the active enzyme from the blood. Immunohistochemical analysis confirmed the presence of ASNase in cells positive for the murine macrophage marker F4/80. To confirm the importance of macrophage populations in ASNase clearance, we depleted mice from phagocytic cells by injection of clodronate liposomes, and studied ASNase biodistribution and kinetics. Indeed, clodronate pretreatment significantly diminished the accumulation of ASNase in the liver, spleen and the bone marrow while doubling the circulatory half-life of serum ASNase activity. We conclude from these experiments that macrophages determine the pharmacokinetics of asparaginase, which raises the question whether rapid clearance of the drug by bone marrow resident macrophages will negatively affect the depletion of asparagine in the bone marrow niche. We previously linked a germline mutation in the gene encoding endosomal protease Cathepsin B to strongly diminished asparaginase degradation in a pediatric ALL patient. To connect the macrophage mediated clearance to the proposed role of Cathepsin B in ASNase degradation, we studied the contribution of this protease in macrophage-mediated degradation of asparaginase. We used cell lines to show that Cathepsin B expression is induced during differentiation from monocytes towards macrophages. This is consistent with our finding that macrophages, but not monocytes, are capable of degrading ASNase. Furthermore, we used both chemical inhibition and RNAi mediated knockdown of Cathepsin B to show that this protease is required for ASNase degradation in these macrophages. Finally, by comparing Cathepsin B knockout mice with wildtype littermates, we demonstrated that loss of Cathepsin B activity significantly delayed clearance of serum asparaginase, consistent with a prominent role for this lysosomal protease in ASNase turnover. In conclusion, by using in vivo imaging we showed that asparaginase is efficiently cleared from the circulation by macrophages. In particular, bone marrow resident macrophages may provide a protective environment for leukemic cells by effectively removing the therapeutic protein from the bone marrow niche. However, both the prominent role of macrophages and the importance of the lysosomal protease Cathepsin B in asparaginase clearance, may allow the rational design of a next generation asparaginase. Disclosures Metselaar: Enceladus Pharmaceuticals: Employment, Equity Ownership.

Description: B cell precursor acute lymphoblastic leukemia (BCP-ALL) is one of the most common malignancies in children. In the period 1991-2013, the Dutch Childhood Oncology Group (DCOG) has completed three treatment trials for childhood ALL: ALL8, 9 and 10, each protocol with stratifications into risk-groups (details: www.skion.nl). Although the cure rates increased in these subsequent trials, relapses still occurred in a significant number of children. Since consecutive upfront treatment protocols usually change at multiple levels, genomic alterations that are associated with relapse may also be variable, which could provide insight into the biology underlying therapy failure and relapse. In this study, we characterized the genetic architecture of relapsed BCP-ALL patients within the context of these three Dutch upfront protocols. We identified 3 patient groups based on upfront treatment as follows: Group-1: patients treated upfront with high-amounts of corticosteroids (CS) and relatively mild additional chemotherapy (ALL9 NHR/HR); Group-2: patients treated with high-amounts of CS and intensive additional chemotherapy (ALL10 MR); Group-3: patients treated with low-amounts of CS and moderately-intensive additional chemotherapy (ALL8 SR/MR, ALL10 SR). The number of high-risk patients that relapsed after ALL8 HR and ALL10 HR chemotherapy courses was too low to be included for analysis. We determined, at relapse, the presence of copy number alterations and sequence mutations in 21 recurrently affected genes involved in B-cell development, cell cycle regulation and RAS signaling, in 123 patients that relapsed after treatment in group-1 (n=56), group-2 (n=20) and group-3 (n=47). The number of CREBBP mutations in patients that relapsed after treatment according to group-1 (ALL9) was significantly lower compared to the other two groups, whereas B-cell development alterations were most common in patients that relapsed after treatment according to group-1, mainly due to a higher number of IKZF1 alterations (Figure 1). The high number of relapsed patients with leukemic clones carrying IKZF1 alterations in patients treated with high-amounts of CS and relatively mild additional chemotherapy is in line with our recent finding that IKZF1 is a key determinant of GC-induced apoptosis in normal and leukemic B-cells, and that loss of IKZF1 function confers resistance to dexamethasone, the major treatment component in group-1 (Marke et al., submitted). Additionally, in the group-2 patients treated with high-amounts of CS and highly intensive additional chemotherapy, a lower percentage IKZF1-deleted clones was detected at relapse, indicating that more GC-resistant, IKZF1-deleted clones are killed by the intense chemotherapy given in addition to CS in group-2 patients. Similarly, in the group-3 patients relapsing after treatment with lower amounts of CS and moderately-intensive additional chemotherapy, the percentage of surviving IKZF1-deleted clones was lower than in patients treated with high-amounts of CS. Taken together, our data indicate that the genetic architecture of relapsed BCP-ALL patients depends on the upfront treatment and, in addition, that the poor-prognostic feature of IKZF1-deletions may be more prominent in upfront treatment with high-amounts of CS and relatively mild additional chemotherapy. Figure 1. The frequency of genetic alterations in studied genes in patients that relapsed after treatment according to group-1, 2 and 3. Genes were grouped by their corresponding pathways. Group-1: patients treated upfront with high-amounts of CS and relatively mild additional chemotherapy (ALL9 NHR/HR); Group-2: patients treated with high-amounts of CS and intensive additional chemotherapy (ALL10 MR); Group-3: patients treated with low-amounts of CS and moderately-intensive additional chemotherapy (ALL8 SR/MR, ALL10 SR). Asterisk showed significant difference between upfront treatment groups, **p

Description: Current risk assessments for treatment of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are based on several clinical and biological criteria, including genomic alterations. Genomic profiling of BCP-ALL in the last few years has substantially extended the number of risk factors that can be used for risk stratification, including a novel entity known as BCR-ABL1 -like or Ph-like ALL. This subgroup of BCR-ABL1-like cases is characterized by the high recurrence of a diverse repertoire of novel gene fusions and mutations which frequently result in enhanced tyrosine kinase and cytokine receptor signaling [Roberts et al., NEJM 2014;371:1005-15]. Leukemia's with these alterations could potentially be targeted with appropriate tyrosine kinase inhibitors. Clinical trials with newly-diagnosed patients carrying these alterations are therefore required, but the large genomic diversity within this group of patients currently provides a major bottleneck. Here, we describe the use of Targeted Locus Amplification (TLA), combined with deep-sequencing to detect fusion genes and sequence mutations relevant for stratification of BCP-ALL. TLA involves a strategy to selectively amplify and sequence regions 〉100 kb around a preselected primer pair by crosslinking of physically proximal genomic sequences [de Vree et al., Nat Biotechnol. 2014;32:1019-25]. Since TLA results in the amplification of all sequences at either end of the primer pair, TLA is highly effective in picking up structural variations including novel fusion partners. Furthermore, breakpoints can be identified from the TLA sequencing data from which targets for detection of minimal residual disease can be directly designed. A total of 31 primer sets targeting 19 recurrently affected genes were designed and multiplexed, including the 'classical' players MLL, RUNX1, TCF3, and IKZF1, the tyrosine kinase genes ABL1, ABL2, PDGFRB, CSF1R, JAK1, JAK2, JAK3, FLT3, and TYK2, and the cytokine signaling genes CRLF2, EPOR, IL7R, TSLP, SH2B3, and IL2RB. Primer sets were chosen such that the most relevant regions were sufficiently covered. As a pilot, viable cells from 46 selected BCP-ALL samples were analysed, including 26 cases with a BCR-ABL1 -like expression profile [Den Boer et al., Lancet Oncol. 2009;10:125-34], of which 6 had a known kinase fusion. 7 Gb of aligned sequence data was obtained for each patient sample. All 21 rearrangements known to be present in these samples were detected by TLA, including rearrangements in ETV6-RUNX1 (n=5), MLL (n=4), TCF3-PBX1 (n=3), CRLF2 (n=4), EBF1-PDGFRB (n=2), BCR-ABL1 (n=1), RCSD1-ABL2 (n=1), and SSBP2 -CSF1R (n=1). For 10 of the fusions sequencing depth was sufficient to extract breakpoint-spanning sequences directly. For two cases with known JAK2 fusions with an unknown partner, the fusion gene was identified (TERF2 and BCR), as was the case for an unknown ABL1 fusion (FOXP1). New fusions were identified in 9 cases, including previously described IGH@-EPOR and TCF3-ZNF384 fusions, and novel kinase activating fusions of MAP3K19-TSLP and HDAC9-FLT3. In addition we identified deletion breakpoint fusions in IKZF1, and sequence mutations in JAK1, JAK3,and IL7R. In total, we detected gene fusions or sequence mutations affecting tyrosine kinase or cytokine receptor signaling in 16 of the 26 cases with a BCR-ABL1 -like expression profile. We conclude that TLA is an effective method for the reliable detection of sequence mutations and structural variations that are relevant for disease prognosis and/or could be targeted by approved kinase inhibiton. Disclosures Simonis: Cergentis BV: Employment. Klous:Cergentis BV: Employment. Yilmaz:Cergentis BV: Employment. Splinter:Cergentis BV: Employment.