Shaking Table Experiment of a Model Slope Subjected to a Pair of Repeated Ground Motions

This paper describes the third of a series of six shaking table experiments conducted as part of ongoing research to evaluate the accuracy and applicability of the Newmark (1965) procedure for computing seismically induced deformation in slopes. A cohesive model slope was shaken by two identical test motions in succession, mimicking a situation that commonly occurs when a preexisting landslide is subjected to strong earthquake shaking. Back analyses of the tests showed that the Newmark (1965) formulation provided moderately accurate estimates of the measured permanent deformations (within 40% to 85% of the maximum measured displacement). The accuracy of the Newmark (1965) formulation was greatest when displacement-dependent degrading yield acceleration was used to model the soil’s transition from peak to residual shear strength. The Newmark analyses were most reliable for the second test that experienced relatively large deformations, and thus where the sliding resistance was controlled by post-peak to residual strength

A case of acute myeloid leukemia with promyelocytic features characterized by expression of a novel RARG-CPSF6 fusion

Key Points Novel RARG-CPSF6 fusion in an AML case with promyelocytic features and no evidence of PML-RARA or X-RARA fusion. Gene fusions involving RARG can initiate AML with promyelocytic morphological features.</jats:p

Kdm6a deficiency restricted to mouse hematopoietic cells causes an age- and sex-dependent myelodysplastic syndrome-like phenotype

Kdm6a/Utx, a gene on the X chromosome, encodes a histone H3K27me3 demethylase that has an orthologue on the Y chromosome (Uty) (Zheng et al. 2018). We previously identified inactivating mutations of Kdm6a in approximately 50% of mouse acute promyelocytic leukemia samples; however, somatic mutations of KDM6A are more rare in human AML samples, ranging in frequency from 2-15% in different series of patients, where their role in pathogenesis is not yet clear. In this study, we show that female Kdm6aflox/flox mice (with allele inactivation initiated by Vav1-Cre in hematopoietic stem and progenitor cells (HSPCs) have a sex-specific phenotype that emerges with aging, with features resembling a myelodysplastic syndrome (MDS). Female Kdm6a-knockout (KO) mice have an age-dependent expansion of their HSPCs with aberrant self-renewal, but they did not differentiate normally into downstream progeny. These mice became mildly anemic and thrombocytopenic, but did not develop overt leukemia, or die from these cytopenias. ChIP-seq and ATAC-seq studies showed only minor changes in H3K27me3, H3K27ac, H3K4me, H3K4me3 and chromatin accessibility between Kdm6a-WT and Kdm6a-KO mice. Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis

A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia

We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers. We performed enhanced exome sequencing on the GCT and the AML M7 from our patient to define the clonal relationship between the two cancers. We found that both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). The mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. In addition, we detected and validated five other shared somatic mutations. The copy-number analysis of the AML exome data revealed an amplification of Chromosome 12p. We also identified a heterozygous germline variant in FANCA (S858R), which is known to be associated with Fanconi anemia but is of uncertain significance here. In summary, our data not only support a common founding clone for these cancers but also suggest that a specific set of distinct genomic alterations (in PTEN and TP53) underlies the rare association between GCT and AML. This association is likely linked to the treatment resistance and extremely poor outcome of these patients. We cannot resolve the clonal evolution of these tumors given limitations of our data

Expression and function of PML-RARA in the hematopoietic progenitor cells of Ctsg-PML-RARA mice

Because PML-RARA-induced acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, many groups have speculated about whether its leukemic cell of origin is a committed myeloid precursor (e.g. a promyelocyte) versus an hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg, and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice), are expressed in the purified KLS cells of these mice (KLS = Kit(+)Lin(-)Sca(+), which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Further, we demonstrate the transcriptional consequences of PML-RARA expression in Ctsg-PML-RARA mice in early myeloid development in other myeloid progenitor compartments [common myeloid progenitors (CMPs) and granulocyte/monocyte progenitors (GMPs)], which have a distinct gene expression signature compared to wild-type (WT) mice. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice and alters the transcriptional signature of these cells, it does not induce their self-renewal. In sum, these results demonstrate that in the Ctsg-PML-RARA mouse model of APL, PML-RARA is expressed in and affects the function of multipotent progenitor cells. Finally, since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in this mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients

Volume Characteristics of Landslides Triggered by the MW 7.8 2016 Kaikōura Earthquake, New Zealand, Derived From Digital Surface Difference Modeling

We use a mapped landslide inventory coupled with a 2‐m resolution vertical difference model covering an area of 6,875 km2 to accurately constrain landslide volume‐area relationships. We use the difference model to calculate the source volumes for landslides triggered by the MW 7.8 Kaikōura, New Zealand, earthquake of 14 November 2016. Of the 29,519 mapped landslides in the inventory, 28,394 are within the analysis area, and of these, we have calculated the volume of 17,256 source areas that are ≥90% free of debris. Of the 28,394 landslides, about 80% are classified as soil or rock avalanches and the remainder as mainly translational slides. Our results show that both the soil avalanches and the rock avalanches, ignoring their source geology, have area to volume power‐law scaling exponents (γ) of 0.921 to 1.060 and 1.040 to 1.138, respectively. These are lower than the γ values of 1.1–1.3 (for soil) and 1.3–1.6 (for rock) reported in the literature for undifferentiated landslide types. They are, however, similar to those γ values estimated from other coseismic landslide inventories. In contrast, for 50 selected rotational, translational (planar slide surfaces), or compound slides, where much of the debris remains in the source area, we found γ values range between 1.46 and 1.47, indicating that their slide surfaces were considerably deeper than those landslides classified as avalanches. This study, like previous studies on coseismic landslides, shows that soil and rock avalanches (disrupted landslides) are the dominant landslide type triggered by earthquakes and that they tend to be shallow.Key PointsWe use a 2‐m resolution vertical difference model to estimate source volumes for 17,256 landslides with sources ≥90% free of debris triggered by the MW7.8 2016 Kaikōura EarthquakeThe model was derived by subtracting a tectonically adjusted pre‐EQ surface model from a post‐EQ model, covering an area of 6,875 km2Landslide trigger mechanism, type/failure mode, and source material are critical for accurate estimation of landslide volumes from source‐area geometriesPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156166/2/jgrf21176.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156166/1/jgrf21176_am.pd