Diagnostic utility of STAT6YE361 expression in classical Hodgkin lymphoma and related entities.

Although the distinction of classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma using morphology and immunostains is straightforward in most instances, occasional cases pose diagnostic challenge. We sought to determine the utility of the novel YE361 STAT6 rabbit monoclonal antibody in Hodgkin lymphoma and diagnostically challenging B- and T-cell non-Hodgkin lymphoma entities with Hodgkin-like features. Cases from seven institutions included: 57 classical Hodgkin lymphomas (31% EBV+), 34 nodular lymphocyte predominant Hodgkin lymphomas, 34 mimicking B- and T-cell non-Hodgkin lymphomas, and 7 reactive lymphoproliferations. After review of histology, STAT6YE361 immunostaining was performed. The intensity and spatial localization of immunopositivity was assessed in neoplastic cells. Additional FISH for programmed death ligand-1 (PD-L1) was performed in one patient in paired treatment-naive and relapse biopsy tissues. Two STAT6YE361 immunopositive cases were examined by whole-exome sequencing after flow sorting to assess mutations in STAT6 pathway genes. Most classical Hodgkin lymphomas showed nuclear staining for STAT6YE361 [46/57 cases (80%)] on Hodgkin cells. Staining was exclusively nuclear in a minority [12/46 (26%)], while dual nuclear and cytoplasmic localization was more common [34/46 (74%)]. In contrast, all nodular lymphocyte predominant Hodgkin lymphomas [0/34 (0%)] were negative for nuclear STAT6YE361 staining on the lymphocyte predominant cells. Within B- and T-cell non-Hodgkin lymphomas, nuclear STAT6YE361 was seen in: B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and in primary mediastinal large B-cell lymphoma. Strong PD-L1 gene amplification was noted in the paired cHL and relapse B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, although STAT6YE361 was negative in both biopsies. Whole-exome sequencing identified mutations in B2M, XPO1, and ITPKB as well CISHP213L (in the STAT pathway) in one classical Hodgkin lymphoma patient positive for nuclear STAT6YE361 although no underlying STAT6 mutations were observed in either sample examined. STAT6YE361 nuclear staining has 100% positive predictive value and 85.7% negative predictive value in confirming or excluding classical Hodgkin lymphoma diagnosis in the distinction from nodular lymphocyte predominant Hodgkin lymphoma and other benign and malignant entities.

Peripheral T-cell lymphomas of follicular helper T-cell type frequently display an aberrant CD3(-/dim)CD4(+) population by flow cytometry: an important clue to the diagnosis of a Hodgkin lymphoma mimic.

Nodal follicular helper T-cell-derived lymphoproliferations (specifically the less common peripheral T-cell lymphomas of follicular type) exhibit a spectrum of histologic features that may mimic reactive hyperplasia or Hodgkin lymphoma. Even though angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma of follicular type share a common biologic origin from follicular helper T-cells and their morphology has been well characterized, flow cytometry of peripheral T-cell lymphomas of follicular type has not been widely discussed as a tool for identifying this reactive hyperplasia/Hodgkin lymphoma mimic. We identified 10 peripheral T-cell lymphomas of follicular type with available flow cytometry data from five different institutions, including two cases with peripheral blood evaluation. For comparison, we examined flow cytometry data for 8 classical Hodgkin lymphomas (including 1 lymphocyte-rich classical Hodgkin lymphoma), 15 nodular lymphocyte predominant Hodgkin lymphomas, 15 angioimmunoblastic T-cell lymphomas, and 26 reactive nodes. Lymph node histology and flow cytometry data were reviewed, specifically for the presence of a CD3(-/dim)CD4(+) aberrant T-cell population (described in angioimmunoblastic T-cell lymphomas), besides other T-cell aberrancies. Nine of 10 (90%) peripheral T-cell lymphomas of follicular type showed a CD3(-/dim)CD4(+) T-cell population constituting 29.3% (range 7.9-62%) of all lymphocytes. Five of 10 (50%) had nodular lymphocyte predominant Hodgkin lymphoma or lymphocyte-rich classical Hodgkin lymphoma-like morphology with scattered Hodgkin-like cells that expressed CD20, CD30, CD15, and MUM1. Three cases had a nodular growth pattern and three others exhibited a perifollicular growth pattern without Hodgkin-like cells. Epstein-Barr virus was positive in 1 of 10 cases (10%). PCR analysis showed clonal T-cell receptor gamma gene rearrangement in all 10 peripheral T-cell lymphomas of follicular type. By flow cytometry, 11 of 15 (73.3%) angioimmunoblastic T-cell lymphomas showed the CD3(-/dim)CD4(+) population (mean: 19.5%, range: 3-71.8%). Using a threshold of 3% for CD3(-/dim)CD4(+) T cells, all 15 nodular lymphocyte predominant Hodgkin lymphoma controls and 8 classical Hodgkin lymphomas were negative (Mann-Whitney P=0.01, F-PTCL vs Hodgkin lymphomas), as were 25 of 26 reactive lymph nodes. The high frequency of CD3(-/dim)CD4(+) aberrant T cells is similar in angioimmunoblastic T-cell lymphomas and peripheral T-cell lymphomas of follicular type, and is a useful feature in distinguishing peripheral T-cell lymphomas of follicular type from morphologic mimics such as reactive hyperplasia or Hodgkin lymphoma.

Informatics guided discovery of surface structure-chemistry relationships in catalytic nanoparticles.

A data driven discovery strategy based on statistical learning principles is used to discover new correlations between electronic structure and catalytic activity of metal surfaces. From the quantitative formulations derived from this informatics based model, a high throughput computational framework for predicting binding energy as a function of surface chemistry and adsorption configuration that bypasses the need for repeated electronic structure calculations has been developed.

Iron sulfide (FeS) nanotubes using sulfurization of hematite nanowires.

We report the phase transformation of hematite (α-Fe2O3) single crystal nanowires to crystalline FeS nanotubes using sulfurization with H2S gas at relatively low temperatures. Characterization indicates that phase pure hexagonal FeS nanotubes were formed. Time-series sulfurization experiments suggest epitaxial growth of FeS as a shell layer on hematite. This is the first report of hollow, crystalline FeS nanotubes with NiAs structure and also on the Kirkendall effect in solid-gas reactions with nanowires involving sulfurization.

Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.

Magnetic anisotropy and engineering of magnetic behavior of the edges in Co embedded graphene nanoribbons.

Using first-principles calculations, we demonstrate the existence of anisotropic ferromagnetic interactions in Co embedded graphene nanoribbons (GNRs). Spin polarization of the edge states is found to alter significantly compared to the metal-free cases. Our findings can all be well-justified as the output of the interplay between the development of an induced spin polarization in the neighborhood of the Co atoms and the maintaining of the polarization picture of the Co-free GNR. Based on our results, we propose an efficient pathway for graphene-based spintronics applications.

Magnetism versus band-gap relationship in diluted magnetic semiconductors: megatom impurity behavior of the magnetic dopant complexes.

An analysis ofab initionumerical results obtained for the total energy of diluted magnetic semiconductors (DMSs) doped with dopant formations of various structural and spin conformations consisting of 2-4 3D transition metal (TM atoms) has revealed that a dopant formation acts as large impurity atom i.e., as amegatom, in a reverse analogy to the process of the adsorption ofsp-atoms onto metallic surfaces. As a result, thed-orbitals of the magnetic dopant formation (themegatom) become hybridized with thesp-bands of the host anions thus creating a number of impurity states which are reflected in the changes of the band gap of the DMS establishing an implicit relationship between the band gap and magnetism. Additional findings also indicate that: (i) the total magnetic momentMtot(α)and the band gapegap(α)which characterize a DMS with a dopant formation in spin conformation (α) do not vary independently from each other but instead form one composite system parameter. (ii) The per dopant-pair magnetic interactions in dopant formations consisting of more than two dopants are smaller than those obtained for an isolated dopant-pair. These are demonstrated with results obtained for GaN doped with 3D-TM dopant formations.

Decoupling 1D and 2D features of 2D sp-nanoribbons-the megatom model.

The dependence of the electron energy band gap on the width of ansp-nanoribbon is investigated using a generalization of the 1D tight binding model for a chain of atoms. Within the proposed generalization, small linear atomic formations along lines perpendicular to the 2D ribbon axis are modeled as single large atoms calledmegatomswhose properties depend on the type, the size and the atomic conformation. Replacement of a 1D chain of atoms by that of the megatoms is accompanied by the incorporation of zeroth order 2D features into the 1D model approximation of the nanoribbon. We use this model to investigate the oscillating band gap of ansp-nanoribbon in terms of the ribbon's width. Results are presented for the width dependence of the energy gap of the zig-zag Si2BN nanoribbons.

Estimation ofsp-dexchange constants revisited.

We present a new computational method for estimating thesp-dexchange constant,Jeffsp-d, applicable to transition metal doped diluted magnetic semiconductors, transition metal oxides, and 2D- and 3D- dichalcogenides. The proposed method is based on results describing the variation of the magnetic features of a doped system with the variation of its magnetization density (M). The results forJeffsp-d(M)obtained with the proposed method are compared with the corresponding results,Jeffsp-d(ΔEVBM), obtained from estimations of the spin electron orbital splitting, ΔEVBM, at the valence band maximum (VBM). The latter is estimated in two ways; either directly from plots of the band structure calculations or by calculating the energy difference between the band-centers of the spin-up and spin-down electron density of states of the doped systems. Despite the inherent drawbacks in these two estimation methods for ΔEVBM, they lead to equivalent results and the correspondingJeffsp-d(ΔEVBM)are in good agreement with theJeffsp-d(M)ones.Ab initioresults obtained for the 2D-MoS2doped with 3d-series transition metals are presented to demonstrate the validity and applicability of the proposed computational schemes for obtainingJeffsp-d. The proposed methods can be utilized as useful tools in the search of new materials for spintronics and valleytronics applications.

Codoping induced enhanced ferromagnetism in diluted magnetic semiconductors.

The experimentally observedd0-magnetism and its subsequent attribution to the presence of structural and topological defects has opened the way for engineering the magnetic properties of diluted magnetic semiconductors (DMSs) and transition metal oxides (TMOs). Doping and codoping constitute the most commonly used processes (either experimentally or theoretically) for developing and studying this type of defect-induced magnetism. The focus of the present review is to highlight the basic features of the defect magnetism which have been observed over diverse systems, while emphasizing the local, holistic and synergistic response of the host materials to their doping and investigating their role in the development of the magnetic coupling (MC) that is developed among the magnetic dopants.Ab initiocomputational results elucidate the local aspects of the MC (charge and spin transfers between dopants and their first nearest neighboring anion ligands) and their relation with holistic processes which are reflected in the band structure, and the shifts of both thed- andp-band centers of the doped material (compared to the undoped one). In view of these results the MC between the magnetic dopants is framed within the newly proposed successive spin polarization and the defect-induced defect-mediated models. The similarities found in the magnetic characteristics between the codoped DMSs/TMOs and the magnetic multilayer systems lends further support to these models which introduce new contributions to the MC that are competitive with the existing classical ones (superexchange, double exchange,s-d&p-dcouplings etc).

High temperature stability, metallic character and bonding of the Si2BN planar structure.

The family of monolayered Si2BN structures constitute a new class of 2D materials exhibiting metallic character with remarkable stability. Topologically, these structures are very similar to graphene, forming a slightly distorted honeycomb lattice generated by a union of two basic motifs with AA and AB stacking. In the present work we study in detail the structural and electronic properties of these structures in order to understand the factors which are responsible for their structural differences as well as those which are responsible for their metallic behavior and bonding. Their high temperature stability is demonstrated by the calculations of finite temperature phonon modes which show no negative contributions up to and beyond 1000 K. Presence of the negative thermal expansion coefficient, a common feature of one-atom thick 2D structures, is also seen. Comparison of the two motifs reveal the main structural differences to be the differences in their bond angles, which are affected by the third nearest neighbor interactions ofcis-transtype. On the other hand, the electronic properties of these two structures are very similar, including the charge transfers occurring between orbitals and between atoms. Their metallicity is mainly due to thepzorbitals of Si with a minor contribution from thepzorbitals of B, while the contribution from thepzorbitals of N atoms is negligible. There is almost no contributions from the Npzelectrons to the energy states near the Fermi level, and they form a band well below it. I.e., thepzelectrons of N are localized mostly at the N atoms and therefore cannot be considered as mobile electrons of thepzcloud. Moreover, we show that due to the relative positions in the energy axis of the atomic energies of thepzorbitals of B, N and Si atoms, the density of states (DOS) of Si2BN can be considered qualitatively as a combination of the DOS of planar hexagonal BN (h-BN) and hypothetically planar silicene (ph-Si). As a result, the Si2BN behaves electronically at the Fermi level as slightly perturbed ph-Si, having very similar electronic properties as silicene, but with the advantage of having kinetic stability in planar form. As for the bonding, the Si-Si bonds are covalent, while theπback donation mechanism occurs for the B-N bonding, in accordance with the B-N bonding in h-BN.

Attenuation of EPO-dependent erythroblast formation by death-associated protein kinase-2.

The adult erythron is maintained via dynamic modulation of erythroblast survival potentials. Toward identifying novel regulators of this process, murine splenic erythroblasts at 3 developmental stages were prepared, purified and profiled. Stage-to-stage modulated genes were then functionally categorized, with a focus on apoptotic factors. In parallel with BCL-X and NIX, death-associated protein kinase-2 (DAPK2) was substantially up-modulated during late erythropoiesis. Among hematopoietic lineages, DAPK2 was expressed predominantly in erythroid cells. In a Gata1-IE3.9int-DAPK2 transgenic mouse model, effects on steady-state reticulocyte and red blood cell (RBC) levels were limited. During hemolytic anemia, however, erythropoiesis was markedly deficient. Ex vivo ana-lyses revealed heightened apoptosis due to DAPK2 at a Kit(-)CD71(high)Ter119(-) stage, together with a subsequent multifold defect in late-stage Kit(-)CD71(high)Ter119(+) cell formation. In UT7epo cells, siRNA knock-down of DAPK2 enhanced survival due to cytokine withdrawal, and DAPK2's phosphorylation and kinase activity also were erythropoietin (EPO)-modulated. DAPK2 therefore comprises a new candidate attenuator of stress erythropoiesis.

EPO receptor circuits for primary erythroblast survival.

EPO functions primarily as an erythroblast survival factor, and its antiapoptotic actions have been proposed to involve predominantly PI3-kinase and BCL-X pathways. Presently, the nature of EPO-regulated survival genes has been investigated through transcriptome analyses of highly responsive, primary bone marrow erythroblasts. Two proapoptotic factors, Bim and FoxO3a, were rapidly repressed not only via the wild-type EPOR, but also by PY-deficient knocked-in EPOR alleles. In parallel, Pim1 and Pim3 kinases and Irs2 were induced. For this survival gene set, induction failed via a PY-null EPOR-HM allele, but was restored upon reconstitution of a PY343 STAT5-binding site within a related EPOR-H allele. Notably, EPOR-HM supports erythropoiesis at steady state but not during anemia, while EPOR-H exhibits near wild-type EPOR activities. EPOR-H and the wild-type EPOR (but not EPOR-HM) also markedly stimulated the expression of Trb3 pseudokinase, and intracellular serpin, Serpina-3G. For SERPINA-3G and TRB3, ectopic expression in EPO-dependent progenitors furthermore significantly inhibited apoptosis due to cytokine withdrawal. BCL-XL and BCL2 also were studied, but in highly responsive Kit(pos)CD71(high)Ter119(neg) erythroblasts, neither was EPO modulated. EPOR survival circuits therefore include the repression of Bim plus FoxO3a, and EPOR/PY343/STAT5-dependent stimulation of Pim1, Pim3, Irs2 plus Serpina-3G, and Trb3 as new antiapoptotic effectors.

Goodenough-Kanamori rules applied to wurtzite crystals.

Goodenough-Kanamori (GK) criteria have provided a significant contribution to our understanding of the importance of the symmetry and the electron orbital characteristics in the development of the magnetic superexchange coupling [antiferromagnetic (AFM) or ferromagnetic (FM)] applied primarily to systems with bond angles of 180° and 90°. In the present work, we quantify and apply the GK criteria to wurtzite systems. Our approach is based on calculations of (i) the spin electron densities of the anions which are first nearest neighbors (1nn) to the magnetic dopants and, (ii) the generalized exchange integrals which are derived by investigating the electronic properties of the systems under a magnetization density constraint. We demonstrate that the magnetization constraint can be used as a probe in investigating the magnetic properties of the materials under magnetization constraints. Our results indicate that the GK criteria applied to diluted magnetic semiconductors and transition metal oxides of wurtzite structures always lead to a FM coupling between two 1nn dopants of the same type. This is justified by ab initio calculations obtained for ZnO and GaN doped with 3d-transition metal dopants.

Signals for stress erythropoiesis are integrated via an erythropoietin receptor-phosphotyrosine-343-Stat5 axis.

Anemia due to chronic disease or chemotherapy often is ameliorated by erythropoietin (Epo). Present studies reveal that, unlike steady-state erythropoiesis, erythropoiesis during anemia depends sharply on an Epo receptor-phosphotyrosine-343-Stat5 signaling axis. In mice expressing a phosphotyrosine-null (PY-null) Epo receptor allele (EpoR-HM), severe and persistent anemia was induced by hemolysis or 5-fluorouracil. In short-term transplantation experiments, donor EpoR-HM bone marrow cells also failed to efficiently repopulate the erythroid compartment. In each context, stress erythropoiesis was rescued to WT levels upon the selective restoration of an EpoR PY343 Stat5-binding site (EpoR-H allele). As studied using a unique primary culture system, EpoR-HM erythroblasts exhibited marked stage-specific losses in Epo-dependent growth and survival. EpoR-H PY343 signals restored efficient erythroblast expansion, and the selective Epo induction of the Stat5 target genes proviral integration site-1 (Pim-1) and oncostatin-M. Bcl2-like 1 (Bcl-x), in contrast, was not significantly induced via WT-EpoR, EpoR-HM, or EpoR-H alleles. In Kit+ CD71+ erythroblasts, EpoR-PY343 signals furthermore enhanced SCF growth effects, and SCF modulation of Pim-1 kinase and oncostatin-M expression. In maturing Kit- CD71+ erythroblasts, oncostatin-M exerted antiapoptotic effects that likewise depended on EpoR PY343-mediated events. Stress erythropoiesis, therefore, requires stage-specific EpoR-PY343-Stat5 signals, some of which selectively bolster SCF and oncostatin-M action.