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// Karthik A. Ganapathi 1 , Vaidehi Jobanputra 1 , Fabio Iwamoto 2 , Preti Jain 1 , Jinli Chen 1 , Luciano Cascione 3 , Odelia Nahum 1 , Brynn Levy 1 , Yi Xie 4 , Pallavi Khattar 5 , Daniela Hoehn 1 , Francesco Bertoni 3 , Vundavalli V. Murty 1 , Stefania Pittaluga 4 , Elaine S. Jaffe 4 , Bachir Alobeid 1 , Mahesh M. Mansukhani 1,* and Govind Bhagat 1,* 1 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA 2 Department of Neurology, Columbia University Medical Center, New York, NY, USA 3 Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland 4 Hematopathology Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA 5 Department of Pathology, New York Medical College, Valhalla, NY, USA * These authors have contributed equally to this work Correspondence to: Govind Bhagat, email: // Mahesh M. Mansukhani, email: // Keywords : dural marginal zone lymphoma, genome, mutations, TNFAIP3, NOTCH2 Received : April 21, 2016 Accepted : May 14, 2016 Published : May 27, 2016 Abstract The dura is a rare site of involvement by marginal zone lymphoma (MZL) and the biology of dural MZL is not well understood. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL.

Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/ or deletion (n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/ NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.

High-throughput gene expression data are often obtained from pure or complex (heterogeneous) biological samples. In the latter case, data obtained are a mixture of different cell types and the heterogeneity imposes some difficulties in the analysis of such data. In order to make conclusions on gene expresssion data obtained from heterogeneous samples, methods such as microdissection and flow cytometry have been employed to physically separate the constituting cell types. However, these manual approaches are time consuming when measuring the responses of multiple cell types simultaneously. In addition, exposed samples, on many occasions, end up being contaminated with external perturbations and this may result in an altered yield of molecular content. In this paper, we model the heterogeneous gene expression data using a Bayesian framework, treating the cell type proportions and the cell-type specific expressions as the parameters of the model. Specifically, we present a novel sequential Monte Carlo (SMC) sampler for estimating the model parameters by approximating their posterior distributions with a set of weighted samples. The SMC framework is a robust and efficient approach where we construct a sequence of artificial target (posterior) distributions on spaces of increasing dimensions which admit the distributions of interest as marginals. The proposed algorithm is evaluated on simulated datasets and publicly available real datasets, including Affymetrix oligonucleotide arrays and national center for biotechnology information (NCBI) gene expression omnibus (GEO), with varying number of cell types. The results obtained on all datasets show a superior performance with an improved accuracy in the estimation of cell type proportions and the cell-type specific expressions, and in addition, more accurate identification of differentially expressed genes when compared to other widely known methods for blind decomposition of heterogeneous gene expression data such as Dsection and the nonnegative matrix factorization (NMF) algorithms. MATLAB implementation of the proposed SMC algorithm is available to download at https://github.com/moyanre/smcgenedeconv.git.

In this paper, we describe a cryogenic, servo-controlled biaxial friction apparatus designed to measure the deformational behaviors of ice. The apparatus is specifically designed to accurately achieve and measure the low differential stresses applicable to deforming ice on earth and on icy satellites. We can apply loads in the range ∼2–1800 kPa and velocities up to 4 mm/s, with resolution of 39 Pa and 0.7 μm, respectively. Precise temperature control, measurement, and insulation allow testing at constant temperature (from −2 to −30 °C) for prolonged periods of time. The apparatus is tested with various plastics as well as with polycrystalline ice samples and the results are consistent with previously published values. Critical components of the instrument are described along with examples of data collection schemes and preliminary results. The flexibility of the design allows for both glaciological and planetary applications over a range of deformational behaviors including friction, anelastic, and viscous.