ALBERT

Description: Manganoquadratite, ideally AgMnAsS3, is a new mineral from the Uchucchacua polymetallic deposit, Oyon district, Catajambo, Lima Department, Peru. It occurs as dark gray, anhedral to subhedral grains up 0.5 mm across, closely associated with alabandite, Mn-rich calcite, Mn-rich sphalerite, proustite, pyrite, pyrrhotite, tennantite, argentotennantite, stannite, and other unnamed minerals of the system Pb-Ag-Sb-Mn-As-S. Manganoquadratite is opaque with a metallic luster and possesses a reddish-brown streak. It is brittle, the Vickers microhardness (VHN10) is 81 kg/mm2 (range 75–96) (corresponding Mohs hardness of 2–2½). The calculated density is 4.680 g/cm3 (on the basis of the empirical formula). In plane-polarized reflected light, manganoquadratite is moderately bireflectant and very weakly pleochroic from dark gray to a blue gray. Internal reflections are absent. Between crossed polars, the mineral is anisotropic, without characteristic rotation tints. Reflectance percentages (Rmin and Rmax) for the four standard COM wavelengths are 29.5, 31.8 (471.1 nm), 28.1, 30.5 (548.3 nm), 27.3, 29.3 (586.6 nm), and 26.0, 28.2 (652.3 nm), respectively.Manganoquadratite is tetragonal, space group P4322, with unit-cell parameters: a = 5.4496(5), c = 32.949(1) Å, V = 978.5(1) Å3, c:a = 6.046, Z = 8. The structure, refined to R1 = 0.0863 for 907 reflections with Fo 〉 4σ(Fo), consists of a stacking along [001] of alabandite-like Mn2S2 layers connected to each to other by a couple of AgAsS2 sheets where As3+ forms typical AsS3 groups, whereas Ag+ cations are fivefold coordinated. The six strongest lines in the observed X-ray powder-diffraction pattern [d in Å (I/I0) (hkl)] are: 3.14 (60) (116), 2.739 (50) (0 0 12), 2.710 (100) (200), 1.927(70) (2 0 12 + 220), 1.645 (25) (3 0 16), and 1.573 (20) (22 12).Electron microprobe analyses gave the chemical formula (on the basis of six atoms) (Ag0.95Cu0.05)∑=1.00 (Mn0.96Pb0.04)∑=1.00(As0.87Sb0.14)∑=1.01S2.99, leading to the simplified formula AgMnAsS3.The name was chosen to indicate the close analogy of the formula and unit-cell dimensions with quadratite, Ag(Cd,Pb)(As,Sb)S3. The new mineral and mineral name have been approved by the Commission on New Minerals, Nomenclature and Classification, IMA 2011-008.

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: Menchettiite, ideally AgPb2.40Mn1.60Sb3As2S12, is a new mineral from the Uchucchacua polymetallic deposit, Oyon district, Catajambo, Lima Department, Peru. It occurs as black, anhedral to subhedral grains up to 200 µm across, closely associated with orpiment, tennantite/tetrahedrite, other unnamed minerals of the system Pb-Ag-Sb-Mn-As-S, and calcite. Menchettiite is opaque with a metallic luster and possesses a black streak. It is brittle, with uneven fracture; the Vickers microhardness (VHN100) is 128 kg/mm2 (range 119–136) (corresponding to a Mohs hardness of 2½–3). The calculated density is 5.146 g/cm3 (on the basis of the empirical formula). In plane-polarized incident light, menchettiite is weakly to moderately bireflectant and weakly pleochroic from dark gray to a dark green. Internal reflections are absent. Between crossed polarizers, the mineral is anisotropic, without characteristic rotation tints. Reflectance percentages (Rmin and Rmax) for the four standard COM wavelengths are 33.1, 39.8 (471.1 nm), 31.8, 38.0 (548.3 nm), 30.9, 37.3 (586.6 nm), and 29.0, 35.8 (652.3 nm), respectively.Menchettiite is monoclinic, space group P21/n, with unit-cell parameters: a = 19.233(2), b = 12.633(3), c = 8.476(2) Å, ß = 90.08(2)°, V = 2059.4(8) Å3, a: b: c 1.522:1:0.671, Z = 2, and it is twinned on {100}. The crystal structure was refined to R = 0.0903 for 2365 reflections with Fo 〉 4s(Fo) and it resulted to be topologically identical to those of ramdohrite, uchucchacuaite, and fizélyite. The six strongest X-ray powder-diffraction lines [d in Å (I/I0) (hkl)] are: 3.4066 (39) (3¯12), 3.4025 (39) (312), 3.2853 (100) (520), 2.8535 (50) (2¯32), 2.8519 (47) (232), and 2.1190 (33) (004). Electron-microprobe analyses gave the chemical formula Ag1.95Cu0.01Pb4.81Mn3.20Fe0.02Zn0.01Sb6.09As3.94Bi0.01S23.95Se0.01, on the basis of 44 atoms and according to the structure refinement results. Menchettiite can be classified among the Sb-rich members of the lillianite homeotypic series, which are described with the general formula AgxPb3-2xSb2+xS6. Besides the heterovalent substitution 2Pb2+ ? Ag+ + Sb3+ taken into consideration by the above formula, two isovalent substitutions relate menchettiite to the other lillianite homeotypes, i.e., Mn2+ ? Pb2+ and As3+ ? Sb3+. The name is after Silvio Menchetti (1937–), Professor of Mineralogy and Crystallography at the University of Florence. The new mineral and mineral name have been approved by the Commission on New Minerals, Nomenclature and Classification, IMA (2011–009).

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: 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: Background Glucocorticoids (GCs) such as prednisolone and dexamethasone are critical components of multi-agent chemotherapy regimens used in the treatment of acute lymphoblastic leukemia (ALL). Children with ALL are stratified into risk groups based on diagnostic features (i.e. age and cytogenetics) and therapy response. It has been established that the initial response to prednisolone is a major prognostic factor. Moreover, at relapse, de novo or acquired resistance to GCs is common and represents an important determinant in treatment failure. Recent studies performed by us and others have identified IKZF1 gene deletions and mutations as an independent prognostic factor that predicts prognosis and treatment outcome of children with B cell precursor ALL (BCP-ALL). These monoallelic IKZF1 gene deletions either affect the whole gene or may result in expression of dominant-negative IKZF1 isoforms due to intragenic deletions. However, it has not been established whether loss of IKZF1 function directly impacts the response to glucocorticoids. Results We examined whether haplodeficiency for Ikzf1 gene expression in mouse lymphocytes affects glucocorticoid-induced apoptosis. Splenocytes from Ikzf1+/- knockout mice were activated with lipopolysaccharide (LPS) and treated with increasing concentrations of either prednisolone or dexamethasone for 48 hours. B-lymphocytes haplodeficient for IKZF1 showed a significantly enhanced survival after treatment with GCs compared to wild type cells, as measured in an MTS assay and by AnnexinV staining. In case of prednisolone, the inhibitory concentration (IC50) was about ∼200-fold higher in the Ikzf1+/- splenocytes as compared to the wild-type cells. Gene expression analysis revealed that Ikzf1+/- splenocytes displayed lower overall expression levels as well as diminished transcriptional activation of several glucocorticoid receptor (GR)-induced target genes (i.e. Sgk1, Irs2, Zfp36L2). Furthermore, in luciferase reporter assays we established that IKZF1 overexpression enhances GR-mediated transcriptional activation in response to prednisolone. Finally, lentivirus-mediated IKZF1-shRNA expression in Nalm6 cell line, which reduces endogenous IKZF1 protein levels to around 50%, inhibits prednisolone and dexamethasone-induced apoptosis, demonstrating that also in human leukemia cells reduced IKZF1 expression levels protect against GC-induced cell death. In conclusion, our data provide evidence that loss of IKZF1 function mediates resistance to glucocorticoid-induced apoptosis, which may contribute to the poor outcome of IKZF1-deleted BCP-ALL. Disclosures: No relevant conflicts of interest to declare.

Description: Resistance to glucocorticoids (GCs) is a major clinical problem in the treatment of acute lymphoblastic leukemia (ALL), but the underlying mechanisms are not well understood. Although mutations in the glucocorticoid receptor (GR) gene can give rise to therapy resistance in vitro, acquired somatic mutations in the GR are rarely encountered in patients. Here we report that the protein encoded by the BTG1 gene, which is frequently deleted in (pediatric) ALL, is a key determinant of GC responsiveness. Using RNA interference, we show that loss of BTG1 expression causes GC resistance both by decimating GR expression and by controlling GR-mediated transcription. Conversely, reexpression of BTG1 restores GC sensitivity by potentiating GC-induced GR expression, a phenomenon known as GR autoinduction. In addition, the arginine methyltransferase PRMT1, a BTG1-binding partner and transcriptional coactivator, is recruited to the GR gene promoter in a BTG1-dependent manner. These results implicate the BTG1/PRMT1 complex in GR-mediated gene expression and reveal that deregulation of a nuclear receptor coactivator complex can give rise to GC resistance. Further characterization of this complex as part of the GR regulatory circuitry could offer novel opportunities for improving the efficacy of GC-based therapies in ALL and other hematologic malignancies.

Description: Abstract 1104 Poster Board I-126 Relapse is the most common cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL), and is difficult to predict from information at diagnosis in the majority of cases. To explore the prognostic impact of recurrent copy number abnormalities on relapse in children diagnosed with precursor-B cell ALL, we performed genome-wide copy number profiling of 34 paired diagnosis-relapse samples. Lesions detected at diagnosis were often absent at relapse, including recurrent targets in precursor-B ALL like PAX5 (not preserved in 2 out of 7 cases with deletions at diagnosis), CDKN2A (not preserved in 1 out of 15 cases), and EBF (not preserved in 2 out of 5 cases), which illustrates that these lesions are often secondary events that are not present in the therapy-resistant progenitor that causes relapse. In contrast, deletions and nonsense mutations in IKZF1, which encodes the lymphoid differentiation factor IKAROS, were highly frequent (38%) and always preserved at time of relapse. Locus-specific copy number screening of IKZF1 in an additional cohort of diagnosis samples from children enrolled in the Dutch treatment protocol DCOG-ALL9 with (n=40) or without (n=51) relapse revealed that IKZF1 deletions were significantly enriched in relapse-prone cases (22.5% vs 3.9%; P=0.007). An independent and unbiased validation cohort of 150 DCOG-ALL9 cases was used to confirm these findings, which established that 28.6% of the cases with IKZF1 deletion at diagnosis developed a relapse. Together, we conclude that deletions of IKZF1 in DCOG-ALL9 treated pediatric precursor-B ALL patients provide a strong prognostic marker for relapse. Disclosures No relevant conflicts of interest to declare.