Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. FINDINGS: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR \u3c 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p \u3c 0·01) compared to controls. INTERPRETATION: This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. FUNDING: NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842

Can disorder induce a finite thermal conductivity in 1D lattices?

We study heat conduction in one dimensional mass disordered harmonic and anharmonic lattices. It is found that the thermal conductivity $\kappa$ of the disordered anharmonic lattice is finite at low temperature, whereas it diverges as $\kappa \sim N^{0.43}$ at high temperature. Moreover, we demonstrate that a unique nonequilibrium stationary state in the disordered harmonic lattice does not exist at all.Comment: 4 pages with 4 eps figure

Structural effects in UO2_2 thin films irradiated with U ions

This work presents the results of a detailed structural characterisation of irradiated and unirradiated single crystal thin films of UO$_2$. Thin films of UO$_2$ were produced by reactive magnetron sputtering onto (0 0 1), (1 1 0) and (1 1 1) single crystal yttria-stabilised zirconia (YSZ) substrates. Half of the samples were irradiated with 110 MeV $^{238}$U$^{31+}$ ions to fluences of 5 $\times$ 10$^{10}$, 5 $\times$ 10$^{11}$ and 5 $\times$ 10$^{12}$ ions/cm$^2$ to induce radiation damage, with the remainder kept for reference measurements. It was observed that as-produced UO$_2$ films adopted the crystallographic orientation of their YSZ substrates. The irradiation fluences used in this study however, were not sufficient to cause any permanent change in the crystalline nature of UO$_2$. It has been demonstrated that the effect of epitaxial re-crystallisation of the induced radiation damage can be quantified in terms of kernel average misorientation (KAM) and different crystallographic orientations of UO$_2$ respond differently to ion irradiation.The irradiation experiment was performed at the Grand Accélérateur National d’Ions Lourds (GANIL) Caen, France, and supported by the French Network EMIR. A.J. Popel acknowledges funding from the UK EPSRC (grant EP/ I036400/1) and Radioactive Waste Management Ltd (formerly the Radioactive Waste Management Directorate of the UK Nuclear Decommissioning Authority, contract NPO004411A-EPS02)

Physiology and transcriptomics of water-deficit stress responses in wheat cultivars TAM 111 and TAM 112

Citation: Reddy, S. K., Liu, S., Rudd, J. C., Xue, Q., Payton, P., Finlayson, S. A., … Lu, N. (2014). Physiology and transcriptomics of water-deficit stress responses in wheat cultivars TAM 111 and TAM 112. Retrieved from http://krex.ksu.eduHard red winter wheat crops on the U.S. Southern Great Plains often experience moderate to severe drought stress, especially during the grain filling stage, resulting in significant yield losses. Cultivars TAM 111 and TAM 112 are widely cultivated in the region, share parentage and showed superior but distinct adaption mechanisms under water-deficit (WD) conditions. Nevertheless, the physiological and molecular basis of their adaptation remains unknown. A greenhouse study was conducted to understand the differences in the physiological and transcriptomic responses of TAM 111 and TAM 112 to WD stress. Whole-plant data indicated that TAM 112 used more water, produced more biomass and grain yield under WD compared to TAM 111. Leaf-level data at the grain filling stage indicated that TAM 112 had elevated abscisic acid (ABA) content and reduced stomatal conductance and photosynthesis as compared to TAM 111. Sustained WD during the grain filling stage also resulted in greater flag leaf transcriptome changes in TAM 112 than TAM 111. Transcripts associated with photosynthesis, carbohydrate metabolism, phytohormone metabolism, and other dehydration responses were uniquely regulated between cultivars. These results suggested a differential role for ABA in regulating physiological and transcriptomic changes associated with WD stress and potential involvement in the superior adaptation and yield of TAM 112

A Plan to Facilitate the Early Career Development of Minority Scholars in the Health Sciences

http://dx.doi.org/10.1080/1937191100374817

Structural effects in UO2 thin films irradiated with U ions

This work presents the results of a detailed structural characterisation of irradiated and unirradiated single crystal thin films of UO2. Thin films of UO2 were produced by reactive magnetron sputtering onto (0 0 1), (1 1 0) and (1 1 1) single crystal yttria-stabilised zirconia (YSZ) substrates. Half of the samples were irradiated with 110 MeV 238U31+ ions to fluences of 5 × 1010, 5 × 1011 and 5 × 1012 ions/cm2 to induce radiation damage, with the remainder kept for reference measurements. It was observed that as-produced UO2 films adopted the crystallographic orientation of their YSZ substrates. The irradiation fluences used in this study however, were not sufficient to cause any permanent change in the crystalline nature of UO2. It has been demonstrated that the effect of epitaxial re-crystallisation of the induced radiation damage can be quantified in terms of kernel average misorientation (KAM) and different crystallographic orientations of UO2 respond differently to ion irradiation

Cornish identities and migration: a multi-scalar approach

The definitive version is available at www.blackwell-synergy.com. 24 month embargo by the publisher. Article will be released July 2009.In this article we argue that theories of transnationalism have value in exploring the historical context of migration and that historical contexts help to shape such theoretical conceptualizations. Historians of migration have now begun to engage more directly with the literature of transnationalism, focusing on the networks that linked settler and home communities. Here we add to this by examining a nineteenth-century migrant community from a British region through the lens of transnationalism, applying the concept to the case of the Cornish, whose economic specialization produced culturally distinct Cornish communities on the mining frontiers of North America, Australia and South Africa. In doing so, we bring together the issues of scale and time. We review the multiple levels of the Cornish transnational space of the late nineteenth century, which exhibited aspects of both core transnationalism and translocalism. This waned, but in the later twentieth century, a renewed interest in a transnational Cornish identity re-emerged, articulating with changing identity claims in Cornwall itself. To capture better the experience of the Cornish over these two very different phases of transnationalism we identify another subset of transnationalism - that of transregionalism.Leverhulme Trus

Pediatric patient with systemic lupus erythematosus & congenital acquired immunodeficiency syndrome: An unusual case and a review of the literature

The coexistence of systemic lupus erythematosus (SLE) in patients with congenital human immunodeficiency virus (HIV) infection is rare. This is a case report of a child diagnosed with SLE at nine years of age. She initially did well on non-steroidal anti-inflammatory agents, hydroxychloroquine, and steroids. She then discontinued her anti-lupus medications and was lost to follow-up. At 13 years of age, her lupus symptoms had resolved and she presented with intermittent fevers, cachexia, myalgias, arthralgias, and respiratory symptoms. Through subsequent investigations, the patient was ultimately diagnosed with congenitally acquired immunodeficiency syndrome (AIDS)

Loss of synergistic transcriptional feedback loops drives diverse B-cell cancers

BACKGROUND: The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping cell-of-origin . Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry. METHODS: We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naïve and memory B-cells) from 36 donor tonsils using \u3e325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and genome copy number (microarrays). FINDINGS: From the resulting data, we identified gains in active chromatin in enhancers/super-enhancers that likely promote unchecked B-cell receptor signaling, including one we validated near the immunoglobulin superfamily receptors FCMR and PIGR. More striking and pervasive was the profound loss of key B-cell identity TFs, tumor suppressors and their super-enhancers, including EBF1, OCT2(POU2F2), and RUNX3. Using a novel approach to identify transcriptional feedback, we showed that these core transcriptional circuitries are self-regulating. Their selective gain and loss form a complex, iterative, and interactive process that likely curbs B-cell maturation and spurs proliferation. INTERPRETATION: Our study is the first to map the transcriptional circuitry of the most common blood cancers. We demonstrate that a critical subset of B-cell TFs and their cognate enhancers form self-regulatory transcriptional feedback loops whose disruption is a shared mechanism underlying these diverse subtypes of B-cell lymphoma. FUNDING: National Institute of Health, Siteman Cancer Center, Barnes-Jewish Hospital Foundation, Doris Duke Foundation