120,666 research outputs found
EVALUATION OF HISTONE DEACETYLASE INHIBITOR EFFECTS ON THYROID CANCER
No full textAbstract
Histone deacetylases (HDACs) play a crucial role in the proper regulation of cellular functions through their connection with chromatin and transcriptional regulation. Alterations in HDAC activity have been reported in several types of cancer encouraging development of HDAC inhibitors (HDACis) for cancer treatment. The antitumor activity of HDACi has been demonstrated, in clinical trials, in both solid and non solid neoplasias at doses well tolerated by patients. However, the molecular basis for their tumor selectivity is unknown. Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, having a poor prognosis and being refractory to conventional chemo- and radiotherapy. To the aim to find an innovative therapy for the treatment of ATCs, we studied the effects of two potent HDACis, SAHA and MS-275, on rat thyroid cell lines transformed by the v-ras-Ki oncogene which is frequently mutated in ATCs. We show that: i) HDAC 1 and HDAC 2 are overexpressed in anaplastic thyroid carcinomas compared to normal thyroid; ii) SAHA and MS-275 induce apoptosis selectively in completely transformed rat thyroid cells; iii) TNF-related apoptosis-inducing ligand (TRAIL) is the main mediator of cell death induced by SAHA; iv) SAHA stabilize TRAIL protein by affecting its proteasome-mediated degradation
Scolytoplatypus lopchuensis Maiti & Saha
No full text11. Scolytoplatypus lopchuensis Maiti & Saha * Scolytoplatypus lopchuensis Maiti & Saha, 2009: 90. Thai distribution: N: Chiang Mai. New to Thailand. New record: Chiang Mai, Doi Inthanon NP, Checkpoint 2, 18° 31.55' N, 98° 29.94' E, 1700 m, MT, 8–15.v.2007 (Y. Areeluck) (1). Other distribution: India (W. Bengal). (2) Taxonomy: In their description of the male, Maiti and Saha (2009) fail to mention the prosternum, which is a valuable taxonomic character in Scolytoplatypus (Beaver & Gebhardt 2006). It is broadly flattened posteriorly, but tapers anteriorly to a sharp point which is more strongly sclerotised. The tapering part bears long, backwardly pointing hairs, and at the tip on each side, a small tuft of short, forwardly pointing hairs. Maiti and Saha (2009) do not mention also the extremely long tufts of hairs on the anterior coxae. These are longer than in any other species of Scolytoplatypus known to us, the longest hairs extending two-thirds of the body length. Biology: Maiti and Saha (2009) list three host species in three different families (Lauraceae, Rutaceae, Symplocaceae). Given the localities listed by Maiti & Saha (2009), and above, probably a montane species. Illustrations: D (Maiti & Saha 2009).Published as part of Beaver, R. A., Sittichaya, W. & Liu, L-Y., 2014, A Synopsis of the Scolytine Ambrosia Beetles of Thailand (Coleoptera: Curculionidae: Scolytinae), pp. 1-82 in Zootaxa 3875 (1) on pages 17-18, DOI: 10.11646/zootaxa.3875.1.1, http://zenodo.org/record/513058
Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent
No full textIntroduction: \ud
Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence. The caspase 8 inhibitor FLIP is an anti-apoptotic protein over-expressed in several cancer types including MPM. The histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) is currently being evaluated in relapsed mesothelioma. We examined the roles of FLIP and caspase 8 in regulating SAHA-induced apoptosis in MPM. \ud
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Methods: \ud
The mechanism of SAHA-induced apoptosis was assessed in 7 MPM cell lines and in a multicellular spheroid model. SiRNA and overexpression approaches were used, and cell death was assessed by flow cytometry, Western blotting and clonogenic assays. Results: RNAi-mediated FLIP silencing resulted in caspase 8-dependent apoptosis in MPM cell line models. SAHA potently down-regulated FLIP protein expression in all 7 MPM cell lines and in a multicellular spheroid model of MPM. In 6/7 MPM cell lines, SAHA treatment resulted in significant levels of apoptosis induction. Moreover, this apoptosis was caspase 8-dependent in all six sensitive cell lines. SAHA-induced apoptosis was also inhibited by stable FLIP overexpression. In contrast, down-regulation of HR23B, a candidate predictive biomarker for HDAC inhibitors, significantly inhibited SAHA-induced apoptosis in only 1/6 SAHA-sensitive MPM cell lines. Analysis of MPM patient samples demonstrated significant inter-patient variations in FLIP and caspase 8 expressions. In addition, SAHA enhanced cisplatin-induced apoptosis in a FLIP-dependent manner. \ud
\ud
Conclusions: \ud
These results indicate that FLIP is a major target for SAHA in MPM and identifies FLIP, caspase 8 and associated signalling molecules as candidate biomarkers for SAHA in this disease. © 2011 Elsevier Ltd. All rights reserved
author-bios-SRD-19-0063.R1 – Supplemental material for The Network Structure of Police Misconduct
No full textSupplemental material, author-bios-SRD-19-0063.R1 for The Network Structure of Police Misconduct by George Wood, Daria Roithmayr and Andrew V. Papachristos in Socius</p
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Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype
Full text linkSuberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor used in the treatment of cutaneous T-cell lymphoma and in clinical trials for treatment of multiple other cancers. A major mode of SAHA metabolism is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To characterize the UGTs active against SAHA, homogenates from HEK293 cell lines overexpressing UGT wild-type or variant UGT were used. The hepatic UGTs 2B17 and 1A9 and the extrahepatic UGTs 1A8 and 1A10 exhibited the highest overall activity against SAHA as determined by
V
max
/K
M
(16 ± 6.5, 7.1 ± 2.2, 33 ± 6.3, and 24 ± 2.4 nL·min
−1.
μg UGT protein
−1
, respectively), with UGT2B17 exhibiting the lowest K
M
(300 μmol/L) against SAHA of any UGT
in vitro
. Whereas the UGT1A8p.Ala173Gly variant exhibited a 3-fold (
P
< 0.005) decrease in glucuronidation activity against SAHA compared with wild-type UGT1A8, the UGT1A8p.Cys277Tyr variant exhibited no detectable glucuronidation activity; a similar lack of detectable glucuronidation activity was observed for the UGT1A10p.Gly139Lys variant. To analyze the effects of the
UGT2B17
gene deletion variant (
UGT2B17
*
2
) on SAHA glucuronidation phenotype, human liver microsomes (HLM) were analyzed for glucuronidation activity against SAHA and compared with
UGT2B17
genotype. HLM from subjects homozygous for
UGT2B17
*
2
exhibited a 45% (
P
< 0.01) decrease in glucuronidation activity and a 75% (
P
< 0.002) increase in K
M
compared with HLMs from subjects homozygous for the wild-type
UGT2B17
*
1
allele. Overall, these results suggest that several UGTs play an important role in the metabolism of SAHA and that UGT2B17-null individuals could potentially exhibit altered SAHA clearance rates with differences in overall response
Expression of the Nonclassical MHC Class I, Saha-UD in the Transmissible Cancer Devil Facial Tumour Disease (DFTD)
Full text linkDevil facial tumour disease (DFTD) is a transmissible cancer that has circulated in the Tasmanian devil population for >25 years. Like other contagious cancers in dogs and devils, the way DFTD escapes the immune response of its host is a central question to understanding this disease. DFTD has a low major histocompatibility complex class I (MHC-I) expression due to epigenetic modifications, preventing host immune recognition of mismatched MHC-I molecules by T cells. However, the total MHC-I loss should result in natural killer (NK) cell activation due to the ‘missing self’. Here, we have investigated the expression of the nonclassical MHC-I, Saha-UD as a potential regulatory or suppressive mechanism for DFTD. A monoclonal antibody was generated against the devil Saha-UD that binds recombinant Saha-UD by Western blot, with limited crossreactivity to the classical MHC-I, Saha-UC and nonclassical Saha-UK. Using this antibody, we confirmed the expression of Saha-UD in 13 DFTD tumours by immunohistochemistry (n = 15) and demonstrated that Saha-UD expression is heterogeneous, with 12 tumours showing intratumour heterogeneity. Immunohistochemical staining for the Saha-UD showed distinct patterns of expression when compared with classical MHC-I molecules. The nonclassical Saha-UD expression by DFTD tumours in vivo may be a mechanism for immunosuppression, and further work is ongoing to characterise its ligand on immune cells
Meghnad Saha: his life in science and politics
No full textThis biography is a short yet comprehensive overview of the life of Meghnad Saha, the mastermind behind the frequently used Saha equations and a strong contributor to the foundation of science in India. The author explores the lesser known details behind the man who played a major role in building scientific institutions in India, developed the breakthrough theory of thermal ionization, and whose fervor about India’s rapid progress in science and technology, along with concern for uplifting his countrymen and optimizing resources, led him to eventually enter politics and identify the mismanagement of many programs of national importance to Parliament. This book is free of most academic technicalities, so that the reader with general scientific knowledge can read and understand it easily. One interested only in Saha’s contribution to physics can pick up just that part and read it. Conversely, the average reader may skip the technical chapters, and read the book without loss of continuity or generality to still get a coherent picture. This work touches on all aspects of Saha’s multidimensional personality, which overflows in the pages of his periodical, Science and Culture,as well as his many speeches, debates and discussions in Parliament, all of which is appropriately conveyed in this book
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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