201 research outputs found
Transcriptomic Profiling Explains Racial Disparities in Pterygium Patients Treated With Doxycycline
No full textCitation: Larrayoz IM, RúaÓ, Velilla S, Martínez A. Transcriptomic profiling explains racial disparities on pterygium patients treated with doxycycline. Invest Ophthalmol Vis Sci
Non-coding NOTCH1 mutations in chronic lymphocytic leukemia; their clinical impact in the UK CLL4 trial
No full textEstrogen reduces aldosterone, upregulates adrenal angiotensin II AT2 receptors and normalizes adrenomedullary Fra-2 in ovariectomized rats
No full textWe studied the effect of ovariectomy and estrogen replacement on expression of adrenal angiotensin II AT 1 and AT 2 receptors, aldosterone content, catecholamine synthesis, and the transcription factor Fos-related antigen 2 (Fra-2). Ovariectomy increased AT 1 receptor expression in the adrenal zona glomerulosa and medulla, and decreased adrenomedullary catecholamine content and Fra-2 expression when compared to intact female rats. In the zona glomerulosa, estrogen replacement normalized AT 1 receptor expression,decreased AT 1B receptor mRNA, and increased AT 2 receptor expression and mRNA. Estrogen treatment decreased adrenal aldosterone content. In the adrenal medulla, the effects of estrogen replacement were:normalized AT 1 receptor expression, increased AT 2 receptor expression, AT 2 receptor mRNA, and tyrosine hydroxylase mRNA, and normalized Fra-2 expression and catecholamine content. We demonstrate that the constitutive adrenal expression of AT 1 receptors, catecholamine synthesis and Fra-2 expression are partially under the control of reproductive hormones. Our results suggest that estrogen treatment decreases aldosterone production through AT 1 receptor downregulation and AT 2 receptor upregulation. AT 2 receptor upregulation and modulation of Fra-2 expression may participate in the estrogen-dependent normalization of adrenomedullary catecholamine synthesis in ovariectomized rats. The AT 2 receptor upregulation and the decrease in AT 1 receptor function and in the production of the fluid-retentive, pro-inflammatory hormone aldosterone partially explain the protective effects of estrogen therapy.We studied the effect of ovariectomy and estrogen replacement on expression of adrenal angiotensin II AT 1 and AT 2 receptors, aldosterone content, catecholamine synthesis, and the transcription factor Fos-related antigen 2 (Fra-2). Ovariectomy increased AT 1 receptor expression in the adrenal zona glomerulosa and medulla, and decreased adrenomedullary catecholamine content and Fra-2 expression when compared to intact female rats. In the zona glomerulosa, estrogen replacement normalized AT 1 receptor expression, decreased AT 1B receptor mRNA, and increased AT 2 receptor expression and mRNA. Estrogen treatment decreased adrenal aldosterone content. In the adrenal medulla, the effects of estrogen replacement were: normalized AT 1 receptor expression, increased AT 2 receptor expression, AT 2 receptor mRNA, and tyrosine hydroxylase mRNA, and normalized Fra-2 expression and catecholamine content. We demonstrate that the constitutive adrenal expression of AT 1 receptors, catecholamine synthesis and Fra-2 expression are partially under the control of reproductive hormones. Our results suggest that estrogen treatment decreases aldosterone production through AT 1 receptor downregulation and AT 2 receptor upregulation. AT 2 receptor upregulation and modulation of Fra-2 expression may participate in the estrogen-dependent normalization of adrenomedullary catecholamine synthesis in ovariectomized rats. The AT 2 receptor upregulation and the decrease in AT 1 receptor function and in the production of the fluid-retentive, pro-inflammatory hormone aldosterone partially explain the protective effects of estrogen therapy.Fil: Macova, Miroslava. National Institute of Mental Health. Department of Health and Human Services; Estados UnidosFil: Armando, Maria Ines. National Institute of Mental Health. Department of Health and Human Services; Estados UnidosFil: Zhou, Jin. National Institute of Mental Health. Department of Health and Human Services; Estados UnidosFil: Baiardi, Gustavo Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Tyurmin, Dmitri. National Institute of Mental Health. Department of Health and Human Services; Estados UnidosFil: Larrayoz Roldan, Ignacio M.. National Institute of Mental Health. Department of Health and Human Services; Estados UnidosFil: Saavedra, Juan M.. National Institute of Mental Health. Department of Health and Human Services; Estados Unido
NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2
No full textThe t(7;11)(p15;p15.4) has been reported to fuse the NUP98 gene (11p15), a component of the nuclear pore complex, with the class-1 homeobox gene HOXA9 at 7p15. This translocation has been associated with myeloid leukemias, predominantly acute myeloid leukemia (AML) M2 subtype with trilineage myelodysplastic features, and with a poor prognosis. The derived fusion protein retains the FG repeat motif of NUP98 N-terminus and the homeodomain shared by the HOX genes, acting as an oncogenic transcription factor critical for leukemogenesis. We report here a new complex t(7;11)-variant, i.e., t(7;11;13;17)(p15;p15;p?;p1?2) in a patient with AML-M2 and poor prognosis. The NUP98-HOXA9 fusion transcript was detected by RT-PCR, suggesting its role in the malignant transformation as it has been postulated for other t(7;11)-associated leukemias. No other fusion transcripts involving the NUP98 or HOXA9 genes were present, although other mechanisms involving several genes on chromosomes 13 and 17 may also be involved. To our knowledge, this is the first t(7;11) variant involving NUP98 described in hematological malignancies
Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells.
No full textState-of-the-art of Heliostat Field Layout Algorithms and their Comparison
No full textAbstractIn this paper a complete review of the most relevant algorithms for the generation of heliostat field layouts is presented. For each of the reviewed algorithms, a description of the layout generation approach, all the input parameters required and the main formulation is provided. The algorithms have been compared for different scenarios covering a range of tower heights, heliostat sizes and acceptance angles (defining to what extent the resulting field is North configuration or surrounding). A robust methodology has been developed, which ensures a fair comparison of the algorithms by analysing the performance of optimized solar fields according to each layout generation method. For this, all the input parameters of each layout generation algorithm are optimized for each scenario prior to comparing the solar field performances. The main conclusion of the present study is that all the analysed layout generation algorithms lead to similar solar field efficiencies when compared for the considered scenarios once they are optimized. Further work is required to check if the algorithms also show similar efficiencies, or to what extent they are similar, when wider scenarios are considered (larger solar field powers, locations, etc.)
The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukemia cells through downregulation of Mcl-1
No full textThe pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose- and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression. However, normal B and T cells were less sensitive than CLL cells (P=0.006 and P<0.001, respectively). SSA altered the splicing of anti-apoptotic MCL-1L to MCL-1s in CLL cells coincident with induction of apoptosis. Overexpression studies in Ramos cells suggested Mcl-1 was important for SSA-induced killing since its expression inversely correlated with apoptosis (P=0.001). IL4 and CD40L, present in patient lymph nodes, are known to protect tumor cells from apoptosis and significantly inhibited SSA, ABT-263 and ABT-199 induced killing following administration to CLL cells (P=0.008). However, by combining SSA with the Bcl-2/Bcl-xL antagonists ABT-263 or ABT-199, we were able to overcome this pro-survival effect. We conclude that SSA combined with Bcl-2/Bcl-xL antagonists may have therapeutic utility for CL
Longitudinal copy number, whole exome and targeted deep sequencing of 'good risk' IGHV-mutated CLL patients with progressive disease
No full textDisease progression in IGHV-M CLL with 'good-risk' cytogenetics is frequently associated with co-evolution of 'poor risk' driver mutations and DNA methylation changes.Drug resistance in IGHV-M CLL may be consequent upon the emergence of an IGHV-U cloneThe biological features of IGHV-M CLL responsible for disease progression are still poorly understood. We undertook a longitudinal study close to diagnosis, pre-treatment and post relapse in thirteen patients presenting with cMBL or Stage A disease and good risk biomarkers (IGHV-M genes, no del(17p) or del(11q) and low CD38 expression) who nevertheless developed progressive disease, of whom ten have required therapy. Using cytogenetics, FISH, genome-wide DNA methylation and copy number analysis together with whole exome, targeted deep- and Sanger sequencing, at diagnosis we identified mutations in established CLL driver genes in nine (69%), non-coding mutations (PAX5 enhancer region) in three, and genomic complexity in two patients. Branching evolutionary trajectories predominated (n=9/13), revealing intra-tumoural epi- and genetic heterogeneity and sub-clonal competition prior to therapy. Of the patients subsequently requiring treatment, two had sub-clonal TP53 mutations that would not be detected by standard methodologies, three qualified for the very-low risk category defined by integrated mutational and cytogenetic analysis and yet had established or putative driver mutations and one patient developed progressive, therapy-refractory disease associated with the emergence of an IGHV-U clone. These data suggest that extended genomic and immunogenetic screening may have clinical utility in patients with apparent good risk disease.Leukemia accepted article preview online, 05 February 2016. doi:10.1038/leu.2016.10
Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia.
No full textThe identification of those genes that are frequently mutated in malignancies is essential for a full understanding of the molecular pathogenesis of these disorders, and often for the provision of markers for the study of disease progression. Recently, mutation of the ASXL1 (additional sex combs 1) gene has been reported in 4 out of 35 patients (11%) with myelodysplastic syndromes (MDS) and in 17 out of 39 patients (43%) with chronic myelomonocytic leukemia (CMML), a disease classified as MDS/myeloproliferative disorder
Proteomics profiling of CLL versus healthy B-cells identifies putative therapeutic targets and a subtype-independent signature of spliceosome dysregulation
No full textChronic lymphocytic leukaemia (CLL) is a heterogeneous B-cell cancer exhibiting a wide spectrum of disease courses and treatment responses. Molecular characterisation of RNA and DNA from CLL cases has led to the identification of important driver mutations and disease sub-types, but the precise mechanisms of disease progression remain elusive. To further our understanding of CLL biology we performed isobaric labelling and mass spectrometry proteomics on 14 CLL samples, comparing them with B-cells from healthy donors (HDB). Of 8694 identified proteins, ~6000 were relatively quantitated between all samples (q<0.01). A clear CLL signature, independent of subtype, of 544 significantly overexpressed proteins relative to HDB was identified, highlighting establishedhallmarks of CLL (eg. CD5, BCL2, ROR1 and CD23 overexpression). Previously unrecognised surface markers demonstrated overexpression (eg. CKAP4, PIGR, TMCC3 and CD75) and three of these (LAX1, CLEC17A and ATP2B4) were implicated in B-cell receptor signalling, which plays an important role in CLL pathogenesis. Several other proteins (eg. Wee1, HMOX1/2, HDAC7 and INPP5F) were identified with significant overexpression that also represent potential targets. Western blotting confirmed overexpression of a selection of these proteins in an independent cohort. mRNA processing machinery were broadly upregulated across the CLL samples. Spliceosome components demonstrated consistent overexpression (p=1.3x10-21) suggesting dysregulation in CLL, independent of SF3B1 mutations. This study highlights the potential of proteomics in the identification of putative CLL therapeutic targets and reveals a subtype-independent protein expression signature in CLL
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