Sub-Nuclear Localization and Tumorigenic Function of the Oncoprotein Dek.

The human DEK gene is overexpressed in a number of malignancies, however its potential function in the context of cancer remains unknown. DEK has been implicated in a diverse set of cellular processes, including regulation of transcription, chromatin architecture, mRNA processing, and cell signaling. Regulation of the participation of DEK in these disparate functions is thought to be achieved through differential post-translational modification. We demonstrate that a fraction of nuclear DEK is acetylated in vivo. Acetylation of DEK results in the accumulation of DEK in interchromatin granule clusters, dense sub-nuclear structures enriched in mRNA processing factors. Overexpression of the acetylase p300/CBP-associated factor was sufficient to cause migration of DEK into interchromatin granule clusters. Inhibition of transcription similarly altered the sub-nuclear distribution of DEK, causing accumulation of DEK in both interchromatin granule clusters, as well as other sub-nuclear structures. The significance of DEK overexpression in melanoma was also addressed. Metastatic melanoma lines displayed remarkably increased expression of DEK as compared to normal melanocytes. Inhibition of DEK expression by shRNA interference revealed two oncogenic contributions of DEK. Knockdown of DEK expression resulted in the induction of the cyclin-dependent kinase inhibitor p21CIP1. In some, but not all melanomas, the expression of p21CIP1 was accompanied by the induction of cellular senescence. These findings suggest that overexpression of DEK may represent an event in melanoma development required to evade tumor suppression through cell cycle arrest and senescence. In addition to its anti-senescence function, DEK overexpression in melanoma also conferred remarkable chemoresistance to both the DNA damaging agent doxorubicin and the BH3 mimetic compound TW-37. This effect was independent of p53, as inhibition of DEK expression did not alter p53 accumulation or activity in response to doxorubicin. Instead, knockdown of DEK expression sensitized melanoma through downregulation of a member of the anti-apoptotic Bcl-2 family, Mcl-1. Knockdown of DEK expression resulted in reduced activity of the mcl-1 promoter and consequently reduced mcl-1 mRNA. These results demonstrate a novel transcriptional mechanism of Mcl-1 overexpression in melanoma that confers remarkable chemoresistance. This work establishes DEK as a melanoma oncoprotein with both anti-senescence and anti-apoptotic functions.Ph.D.ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/75982/1/mkhodado_1.pd

The Solid Phase Extraction of Some Metal Ions Using Palladium Nanoparticles Attached to Silica Gel Chemically Bonded by Silica-Bonded N-Propylmorpholine as New Sorbent prior to Their Determination by Flame Atomic Absorption Spectroscopy

In this research at first palladium nanoparticle attached to a new chemically bonded silica gel has been synthesized and has been characterized with different techniques such as X-ray diffraction (XRD), fourier transform infrared (FT-IR), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). Then, this new sorbent (chemically modified silica gel with N-propylmorpholine (PNP-SBNPM)) was efficiently used for preconcentration of some metal ions in various food samples. The influence of effective variables including mass of sorbent, flow rate, pH of sample solutions and condition of eluent such as volume, type and concentration on the recoveries of understudy metal ions were investigated. Following the optimization of variables, the interfering effects of some foreign ions on the preconcentration and determination of the investigated metal ions described. At optimum values of variables, all investigated metal ions were efficiently recovered with efficiency more than 95%, relative standard deviation (RSD) between 2.4 and 2.8, and detection limit in the range of 1.4–2.7 ng mL−1. The present method is simple and rapidly applicable for the determination of the understudied metal ions (ng mL−1) in different natural food samples

Effect of age on reproductive performance in female Caspian brown trout (Salmo trutta caspious, Kessler 1877)

Caspian brown trout (Salmo trutta caspius) is one of the economically valuable species in the Caspian Sea.Artificial propagation and production of larvae are the main problems in the early culture of this species.The purpose of this paper is to study the effect of reproductive performance of female broods on opposition reproduction efficiency in Caspian brown trout in the breeding season of 2009. Three groups of female broods (4, 5 and 6 years old) were fertilized with 9 male fish individually. The results showed that,6 year old females have maximum body weight (2150.0 ± 86.6 g), total length (59±2 cm), eggs weight (255.0 ± 30.51 g), egg size (5.37 ± 0.058 mm) and absolute fecundity rate (3060 ± 366.15), while highest average number of ovules in each gram of body weight (16.33 ± 0.58) and relative fecundity (2.08 ± 0.12) belonged to 4 years old females. There were significant differences in mean fertilization rate and survival rate until absorption of yolk sack stage (p<0.05) among the treatments studied. The present study showed that the eggs produced from fertilization of 6 year old female eggs and male mixed milt showed maximum average fertilization percentage (97.5 %), survival rate until eyed stage (92%), hatching percentage (93%), and survival rate until absorption of yolk sack (94.5%)

Transcript-indexed ATAC-seq for precision immune profiling.

T cells create vast amounts of diversity in the genes that encode their T cell receptors (TCRs), which enables individual clones to recognize specific peptide-major histocompatibility complex (MHC) ligands. Here we combined sequencing of the TCR-encoding genes with assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. By using this approach, termed transcript-indexed ATAC-seq (T-ATAC-seq), we identified epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers and primary leukemic T cells from patient samples. In peripheral blood CD4+ T cells from healthy individuals, we identified cis and trans regulators of naive and memory T cell states and found substantial heterogeneity in surface-marker-defined T cell populations. In patients with a leukemic form of&nbsp;cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and nonleukemic regulatory pathways in T cells from the same individual by allowing separation of the signals that arose from the malignant clone from the background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity and immunotherapy

Presumed stromal graft rejection after automated lamellar therapeutic keratoplasty: case report

PURPOSE: To describe the development of presumed immune-mediated stromal rejection after automated lamellar therapeutic keratoplasty (ALTK) and its reversal after initiation of intensive topical corticosteroid therapy. METHODS: Observational case report. RESULTS: Stromal edema localized in the graft developed 42 days after ALTK for Avellino corneal dystrophy in a 65-year-old man. After one week of intensive topical corticosteroids, complete reversal of graft edema occurred, with full recovery of visual function. CONCLUSION: The clinical appearance and response to therapy in this case supported the diagnosis of immune-mediated stromal rejection. Ophthalmologists should be aware that stromal rejection may occur in lamellar corneal grafts

Improving the Performance of Thinning Algorithms with Directed Rooted Acyclic Graphs

In this paper we propose a strategy to optimize the performance of thinning algorithms. This solution is obtained by combining three proven strategies for binary images neighborhood exploration, namely modeling the problem with an optimal decision tree, reusing pixels from the previous step of the algorithm, and reducing the code footprint by means of Directed Rooted Acyclic Graphs. A complete and open-source benchmarking suite is also provided. Experimental results confirm that the proposed algorithms clearly outperform classical implementations

Immunodominant T Cell Determinants of Aquaporin-4, the Autoantigen Associated with Neuromyelitis Optica

Autoantibodies that target the water channel aquaporin-4 (AQP4) in neuromyelitis optica (NMO) are IgG1, a T cell-dependent Ig subclass. However, a role for AQP4-specific T cells in this CNS inflammatory disease is not known. To evaluate their potential role in CNS autoimmunity, we have identified and characterized T cells that respond to AQP4 in C57BL/6 and SJL/J mice, two strains that are commonly studied in models of CNS inflammatory diseases. Mice were immunized with either overlapping peptides or intact hAQP4 protein encompassing the entire 323 amino acid sequence. T cell determinants identified from examination of the AQP4 peptide (p) library were located within AQP4 p21-40, p91-110, p101-120, p166-180, p231-250 and p261-280 in C57BL/6 mice, and within p11-30, p21-40, p101-120, p126-140 and p261-280 in SJL/J mice. AQP4-specific T cells were CD4+ and MHC II-restricted. In recall responses to immunization with intact AQP4, T cells responded primarily to p21-40, indicating this region contains the immunodominant T cell epitope(s) for both strains. AQP4 p21-40-primed T cells secreted both IFN-γ and IL-17. The core immunodominant AQP4 21-40 T cell determinant was mapped to residues 24-35 in C57BL/6 mice and 23-35 in SJL/J mice. Our identification of the AQP4 T cell determinants and characterization of its immunodominant determinant should permit investigators to evaluate the role of AQP4-specific T cells in vivo and to develop AQP4-targeted murine NMO models

Cyclophosphamide Chemotherapy Sensitizes Tumor Cells to TRAIL-Dependent CD8 T Cell-Mediated Immune Attack Resulting in Suppression of Tumor Growth

Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. Methods and Findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies. Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion

Документы архива Учреждения образования «Белорусский государственный медицинский университет» за 1976 – 2013 гг.: организация работ по комплектованию, обеспечению сохранности и использованию : реферат к дипломной работе / Ольга Викторовна Лобач; БГУ, Исторический факультет, Кафедра источниковедения; науч. рук. Яцкевич Д.Л.

Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0–4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P &lt; 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy