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Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs., Funding: Institute for Regenerative Medicine, Karolinska Institute Doctoral Edu-cation (KID) [2-1293/2014, 2021-00480]; Stiftelsen Clas Gro-schinskys Minnesfond [M16 50]; Knut and Alice Wallenberg Foundation [KAW 2020.0102]; Cancer Research KI; Incyte Biosciences Nordic; Blodcancerfonden; Nordic Cancer Union and Cancer Foundation Finland

Several studies have shown that global 3D models of the compression wave speed in the Earth's mantle can provide superior first P travel time predictions at both regional and teleseismic distances. However, given the variable data quality and uneven data sampling associated with this type of model, it is essential that there be a means to calculate high-quality estimates of the path-dependent variance and covariance associated with the predicted travel times of ray paths through the model. In this paper, we show a methodology for accomplishing this by exploiting the full model covariance matrix. Typical global 3D models have on the order of 1/2 million nodes, so the challenge in calculating the covariance matrix is formidable: 0.9 TB storage for 1/2 of a symmetric matrix, necessitating an Out-Of-Core (OOC) blocked matrix solution technique. With our approach the tomography matrix (G which includes Tikhonov regularization terms) is multiplied by its transpose (GTG) and written in a blocked sub-matrix fashion. We employ a distributed parallel solution paradigm that solves for (GTG)-1 by assigning blocks to individual processing nodes for matrix decomposition update and scaling operations. We first find the Cholesky decomposition of GTG which is subsequently inverted. Next, we employ OOC matrix multiplication methods to calculate the model covariance matrix from (GTG)-1 and an assumed data covariance matrix. Given the model covariance matrix we solve for the travel-time covariance associated with arbitrary ray-paths by integrating the model covariance along both ray paths. Setting the paths equal yields the variance for that path., Published in the Proceedings of the 2011 Monitoring Research Review - Ground-Based Nuclear Explosion Monitoring Technologies, 13-15 September 2011, Tucson, AZ. Volume I. Sponsored by the Air Force Research Laboratory (AFRL) and the National Nuclear Security Administration (NNSA). U.S. Government or Federal Rights License

To test the hypothesis that high quality 3D Earth models will produce seismic event locations that are more accurate and more precise than currently used 1D and 2/2.5D models, we are developing a global 3D P wave velocity model of the Earth's crust and mantle using seismic tomography. In this paper, we present the most recent version of our model, SALSA3D (SAndia LoS Alamos 3D) version 1.7, and demonstrate its ability to reduce mislocations for a large set of realizations derived from a carefully chosen set of globally-distributed ground truth events, compared to existing models and/or systems. Our model is derived from the latest version of the Ground Truth (GT) catalog of P and Pn travel time picks assembled by Los Alamos National Laboratory. To prevent over-weighting due to ray path redundancy and to reduce the computational burden, we cluster rays to produce representative rays. Reduction in the total number of ray paths is 50%. The model is represented using the triangular tessellation system described by Ballard et al. (2009), which incorporates variable resolution in both the geographic and radial dimensions. For our starting model, we use a simplified layer crustal model derived from the NNSA Unified model in Eurasia and Crust 2.0 model everywhere else, over a uniform ak135 mantle. Sufficient damping is used to reduce velocity adjustments so that ray path changes between iterations are small. We obtain proper model smoothness by using progressive grid refinement, refining the grid only in areas where the data warrant it. In previous versions of SALSA3D, we based this refinement on velocity changes from previous model iterations. For version 1.7, we utilize the diagonal of the model resolution matrix to control where grid refinement occurs, resulting in more consistent and continuous areas of refinement than before., Published in the Proceedings of the 2011 Monitoring Research Review - Ground-Based Nuclear Explosion Monitoring Technologies, 13-15 September 2011, Tucson, AZ. Volume I. Sponsored by the Air Force Research Laboratory (AFRL) and the National Nuclear Security Administration (NNSA). U.S. Government or Federal Rights License

To test the hypothesis that high quality 3D Earth models will produce seismic event locations which are more accurate and more precise, we are developing a global 3D P wave velocity model of the Earth s crust and mantle using seismic tomography. In this paper, we present the most recent version of our model, SALSA3D (SAndia LoS Alamos) version 1.4, and demonstrate its ability to reduce mislocations for a large set of realizations derived from a carefully chosen set of globally-distributed ground truth events., Published in Proceedings of the 2010 Monitoring Research Review - Ground-Based Nuclear Explosion Monitoring Technologies, 21-23 September 2010, Orlando, FL. Volume I. Sponsored by the Air Force Research Laboratory (AFRL) and the National Nuclear Security Administration (NNSA). U.S. Government or Federal Rights License

Increasingly, nuclear explosion monitoring is focusing on detection, location, and identification of small events recorded at regional distances. Because Earth structure is highly variable on regional scales, locating events accurately at these distances requires the use of region-specific models to provide accurate travel times. Improved results have been achieved with composites of 1D models and with approximate 3D models with simplified upper mantle structures, but both approaches introduce nonphysical boundaries that are problematic for operational monitoring use. Ultimately, what is needed is a true, seamless 3D model of the Earth. Towards that goal, we have developed a 3D tomographic model of the P velocity of the crust and upper mantle for the region of southcentral Asia centered around the Tibetan Plateau. Our model is derived from almost 140,000 Pn picks for more than 5300 events recorded at 563 stations from a Ground Truth (GT) dataset assembled by Los Alamos National Laboratory (LANL). Our starting model is the a priori model of East Asia developed by LANL, which is based on various global and regional studies. The topmost layers come from the Laske and Masters global sedimentary model from 1997. As our dataset lacks the resolution to improve this sedimentary portion of our model, we fix the velocity and depth of these layers, as well as the depths of the major mantle discontinuities (Moho, 410 km, 660 km). We invert for P velocities from the crust down through the upper mantle, along with source and receiver terms to account for the effects of event mislocation and fine-scale structure near the receiver not accounted for in the crustal model. Forward calculations are made using our own implementation of the Um and Thurber ray pseudo-bending approach (Ballard, 2008, these Proceedings) with full enforcement of Snell's Law in 3D at the major discontinuities., Published in the Proceedings of the 30th Monitoring Research Review: Ground-Based Nuclear Explosion Monitoring Technologies, 23-25 Sep 2008, Portsmouth, VA sponsored by the National Nuclear Security Administration (NNSA) and the Air Force Research Laboratory (AFRL). The original document contains color images.

Pseudo-bending is an algorithm for calculating seismic travel time through complex 3D velocity models. The algorithm was originally proposed by Um and Thurber (1987) and later extended by Zhao et al. (1992) to account for first order velocity discontinuities. We have modified Zhao's method of handling discontinuities by implementing a two-dimensional (2D) minimization algorithm that searches for the point on the velocity discontinuity surface where Snell's Law is satisfied. Further, our implementation reduces the likelihood that the pseudo-bending algorithm will return a local minimum by starting the ray calculation from several different starting rays. Specifically, interfaces are defined that include first order discontinuities plus additional interfaces at levels of the model where local minima might be generated. Rays are computed that are constrained to bottom in each layer between these interfaces. The computed rays might be reflected off the top of the layer, turn within the layer, or diffract along the interface at the bottom of the layer. The computed ray that is seismologically valid and that has the shortest travel time is retained. The modifications we have made to the algorithm have made it more accurate and robust but have also made it more computationally expensive. To mitigate this impact, we have implemented our software in a distributed parallel computing environment, which makes possible the calculation of many rays simultaneously., Presented at the Conference on Monitoring Research Review: Ground-Based Nuclear Explosion Monitoring Technologies (30th), held in Portsmouth, VA, on 23-25 Sep 2008. Published in the proceedings of the conference, p338-346, 2008. Sponsored in part by the National Nuclear Security Administration (NNSA). The original document contains color images.