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Uzun, Fatih, and Alexander M. Korsunsky. "The Use of Surface Topography for the Identification of Discontinuous Displacements Due to Cracks." Metals 10, no. 8 (August 2, 2020): 1037. http://dx.doi.org/10.3390/met10081037.
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The determination of three components of displacements at material surfaces is possible using surface topography information of undeformed (reference) and deformed states. The height digital image correlation (hDIC) technique was developed and demonstrated to achieve micro-level in-plane resolution and nanoscale out-of-plane precision. However, in the original formulation hDIC and other topography-based correlation techniques perform well in the determination of continuous displacements. In the present study of material deformation up to cracking and filan failure, the ability to identify discontinuous triaxial displacements at emerging discontinuities is important. For this purpose, a new method reported herein was developed based on the hDIC technique. The hDIC solution procedure comprises two stages, namely, integer-pixel level correlation and sub-pixel level correlation. In order to predict the displacement and height changes in discontinuous regions, a smoothing stage was inserted between the two main stages. The proposed method determines accurately the discontinuous edges, and the out-of-plane displacements become sharply resolved without any further intervention in the algorithm function. High computational demand required to determine discontinuous displacements using high density topography data was tackled by employing the graphics processing unit (GPU) parallel computing capability with the paging approach. The hDIC technique with GPU parallel computing implementation was applied for the identification of discontinuous edges in an aluminium alloy dog bone test specimen subjected to tensile testing up to failure.
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Uzun, Fatih, and Alexander M. Korsunsky. "The height Digital Image Correlation (hDIC) technique for the identification of triaxial surface deformations." International Journal of Mechanical Sciences 159 (August 2019): 417–23. http://dx.doi.org/10.1016/j.ijmecsci.2019.06.014.
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Uzun, Fatih, Alexey I. Salimon, Eugene S. Statnik, Cyril Besnard, Jingwei Chen, Thomas Moxham, Enrico Salvati, Zifan Wang, and Alexander M. Korsunsky. "Polar transformation of 2D X-ray diffraction patterns and the experimental validation of the hDIC technique." Measurement 151 (February 2020): 107193. http://dx.doi.org/10.1016/j.measurement.2019.107193.
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Bradbury, Charlotte A., Farhat L. Khanim, Priyanka Mehta, Rachel E. Hayden, Charles F. Craddock, Chris M. Bunce, and Bryan M. Turner. "Characterisation of Histone Deacetylase (HDAC) Expression Profiles in Acute Myeloid Leukaemia: A Basis for the Development of Targeted Therapy Using Histone Deacetylase Inhibitors." Blood 104, no. 11 (November 16, 2004): 1123. http://dx.doi.org/10.1182/blood.v104.11.1123.1123.
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Abstract Post-translational modifications of chromatin structure are recognised as having a potential role in the pathogenesis of acute myeloid leukaemia (AML). Histone deacetylases play a central role in determining the acetylation status of histones and are emerging as novel targets in AML therapy. Histone deacetylase inhibitors (HDIs) inhibit growth of primary AML blasts in vitro and demonstrate clinical activity in patients with relapsed AML. To date, three major classes of HDACs have been characterised which differ in their susceptibility to HDIs. However, little is known of the pattern of HDAC expression in AML and this limits the rational use of HDIs in this disease. We have analysed the pattern of class I, II and III HDAC expression in AML cell lines, primary AML blasts and CD34+ selected progenitors from cord blood and normal donors by real time quantitative PCR(RT-PCR). RT-PCR analyses demonstrated consistently increased expression in AML blasts of two HDACs compared with proliferating CD34+ve cells from cord blood (n=5) . HDAC2 (class I HDAC) was more highly expressed in 3/3 myeloid cell lines and 20/24 primary AML samples, compared to cord blood CD 34+ve cells. SIRT1 (class III HDAC) was also more highly expressed in 3/3 myeloid cell lines and 24/24 primary AMLs. In contrast, no marked differences were detected in expression of HDAC1, 3, 4, 5, 6, 7, 9, 10, 11 and SIRT 2–6. We therefore studied the impact of sodium valproate (SV), an HDI with reported activity in AML, on HDAC activity and expression. SV treatment resulted in time and dose dependent increases in histone acetylation and specific methylation at H3K4, in both AML cell lines and primary AML cells. We have shown that the mechanism of the increased methylation at H3K4 is partly a result of the preference of the methyltransferase enzyme for acetylated histones. Using quantitative RT-PCR we found that SV treatment of HL-60 cells resulted in increased expression of the gene for MLL, an enzyme known to be capable of methylating H3K4. These changes in chromatin were associated with dose dependent cell killing. Significant (p<0.001, n=10) in vitro killing of primary AML blasts was observed at 1 mM SV and killing was enhanced by the addition of ATRA. However, histone modifications were observed in HL-60 cells at doses that had little effect upon cell viability or proliferation. We have immunoprecipitated complexes containing HDACs 1, 2 and 3 and assayed their enzymatic activity using a tritium labelled H4 peptide substrate. By this method, 1mM SV was potent at inhibiting HDACs 1, 2 and 3 activity. We have also studied the effects of SV on HDAC expression (all three classes) by RT-PCR in HL60 cells at 15 mins, 1h, 4h and 8h. A small number of HDACs were consistently and significantly upregulated by treatment with SV, TSA, Butyrate and SAHA. In contrast, the expression levels of HDAC2 and SIRT1 were relatively unchanged. These changes in HDAC expression may contribute to HDI resistance with continuous therapy. These data provide information which may be of value in determining choice of HDACis in Phase I/II studies in AML. They also identify increased histone methylation as a potentially important outcome of HDI treatment.
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Fiskus, Warren, Rekha Rao, Pravina Fernandez, Bryan Herger, Yonghua Yang, Jianguang Chen, Ravindra Kolhe, et al. "Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor–resistant acute myeloid leukemia cells." Blood 112, no. 7 (October 1, 2008): 2896–905. http://dx.doi.org/10.1182/blood-2007-10-116319.
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Abstract Hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activity against human acute leukemia. Here we describe HA-HDI–resistant human acute myeloid leukemia (AML) HL-60 (HL-60/LR) cells that are resistant to LAQ824, vorinostat, LBH589, and sodium butyrate. HL-60/LR cells show increased expression of HDACs 1, 2, and 4 but lack HDAC6 expression, with concomitant hyperacetylation of heat shock protein 90 (hsp90). Treatment with HA-HDI failed to further augment hsp90 acetylation, or increase the levels of p21 or reactive oxygen species (ROSs), in HL-60/LR versus HL-60 cells. Although cross-resistant to antileukemia agents (eg, cytarabine, etoposide, and TRAIL), HL-60/LR cells are collaterally sensitive to the hsp90 inhibitor 17-AAG. Treatment with 17-AAG did not induce hsp70 or deplete the hsp90 client proteins AKT and c-Raf. HL-60/LR versus HL-60 cells display a higher growth fraction and shorter doubling time, along with a shorter interval to generation of leukemia and survival in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, resistance of AML cells to HA-HDIs is associated with loss of HDAC6, hyperacetylation of hsp90, aggressive leukemia phenotype, and collateral sensitivity to 17-AAG. These findings suggest that an hsp90 inhibitor-based antileukemia therapy may override de novo or acquired resistance of AML cells to HA-HDIs.
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Schioppa, Tiziana, Hoang Oanh Nguyen, Laura Tiberio, Francesca Sozio, Carolina Gaudenzi, Mauro Passari, Annalisa Del Prete, Daniela Bosisio, and Valentina Salvi. "Inhibition of Class I Histone Deacetylase Activity Blocks the Induction of TNFAIP3 Both Directly and Indirectly via the Suppression of Endogenous TNF-α." International Journal of Molecular Sciences 23, no. 17 (August 28, 2022): 9752. http://dx.doi.org/10.3390/ijms23179752.
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Histone deacetylase inhibitors (HDIs) are promising drugs for the treatment of inflammatory diseases. However, their therapeutical exploitation is slowed down by severe adverse manifestations that can hardly be foreseen, mainly due to incomplete knowledge of how HDIs impact the delicate balance of inflammatory mediators. In this work, we characterized the effects of the HDI trichostatin A (TSA) on the expression of TNFAIP3, which is a crucial inhibitor of the classical NF-kB pathway and an LPS-induced negative feedback regulator. The accumulation of TNFAIP3 mRNA after LPS stimulation showed biphasic behavior, with one wave within the first hour of stimulation and a second wave several hours later, which were both reduced by TSA. By using inhibition and knockdown approaches, we identified two temporally and mechanistically distinct modes of action. The first wave of TNAIP3 accumulation was directly blunted by the histone deacetylase (HDAC) blockade. By contrast, the second wave was decreased mainly because of the lack of endogenous TNF-α induction, which, in turn, depended on the intact HDAC activity. In both cases, class I HDACs appeared to play a nonredundant role, with HDAC3 required, but not sufficient, for TNF-α and TNFAIP3 induction. In addition to TNFAIP3, TNF-α is known to induce many response genes that orchestrate the inflammatory cascade. Thus, suppression of TNF-α may represent a general mechanism through which HDIs regulate a selected set of target genes.
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Feng, Mei. "Towards a cultural model of qi in TCM." Review of Cognitive Linguistics 19, no. 1 (April 28, 2021): 1–25. http://dx.doi.org/10.1075/rcl.00074.fen.
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Abstract This paper aims to construct a cultural model of qi in Traditional Chinese Medicine (TCM) by probing into its conceptual metaphors based on a contextualized semantic analysis of qi in Huang Di’s Inner Classic (HDIC). It is found that there are eight conceptual metaphors of qi, each involving experiential correlation between source and target concept. To be specific, cause for effect builds up a major metonymic basis for the metaphorical mappings from the source concept of qi (i.e., substance) to the target concepts, including physiological function, breathing, climate, pathogenic factor, disease/syndrome, odor, property of drugs and time. It is worth special noting that time is understood in terms of the motion of qi in TCM. The conceptual metaphor time is qi is Chinese culture-specific. On the whole, conceptual metaphors of qi form a conceptual network and further constitute a cultural model: qi as the substance origin of human life is believed in TCM to function by ceaseless motion, giving rise to wellness or illness. This cultural model reflects a pair of inseparable concepts in ancient Chinese philosophy, viz. substance and (its) function, with the former being primary, essential and original, while the latter, secondary, concomitant and derivational.
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이케다 쇼주. "『新撰字鏡』本文解読上の諸問題 -HDICの紹介とその活用-." Kugyol Studies ll, no. 38 (February 2017): 39–56. http://dx.doi.org/10.17001/kugyol.2017..38.003.
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Li, Wenbo, and Zheng Sun. "Mechanism of Action for HDAC Inhibitors—Insights from Omics Approaches." International Journal of Molecular Sciences 20, no. 7 (April 1, 2019): 1616. http://dx.doi.org/10.3390/ijms20071616.
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Histone deacetylase inhibitors (HDIs) are a class of prominent epigenetic drugs that are currently being tested in hundreds of clinical trials against a variety of diseases. A few compounds have already been approved for treating lymphoma or myeloma. HDIs bind to the zinc-containing catalytic domain of the histone deacetylase (HDACs) and they repress the deacetylase enzymatic activity. The broad therapeutic effect of HDIs with seemingly low toxicity is somewhat puzzling when considering that most HDIs lack strict specificity toward any individual HDAC and, even if they do, each individual HDAC has diverse functions under different physiology scenarios. Here, we review recent mechanistic studies using omics approaches, including epigenomics, transcriptomics, proteomics, metabolomics, and chemoproteomics, methods. These omics studies provide non-biased insights into the mechanism of action for HDIs.
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Lasdiyanti, Mita, Eka N. Kencana, and Putu Suciptawati. "Modeling Human Development Index of Bali with Spatial Panel Data Regression." European Journal of Engineering Research and Science 4, no. 5 (May 28, 2019): 132–37. http://dx.doi.org/10.24018/ejers.2019.4.5.1312.
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Human development index (HDI) is an index that represents the successfulness of human development in a region. For Bali, one of 34 provinces in Indonesia, the progress of HDI in the period 2010–2017 showed an increasing trend. In the year 2010, the Bali’s HDI is accounted for 70.10, gradually increase to 74.30 in the year 2017. However, in 2017 there are some regions with their HDIs are below of Bali’s HDI, namely Jembrana, Buleleng, Klungkung, Bangli, and Karangasem. The aim of this work is to model the HDI of 9 regencies of Bali so that the main determinant to increase the HDIs especially for the regencies with lower HDIs could be determined. The model consists of one dependent variable (HDI) with three indicators as the independent ones, there are (a) life expectancy, (b) education, and (b) standard of living. By applying spatial panel data analysis, five models were built i.e. CEM, FEM (individual), FEM (time), REM, and spatial error FEM to determine the effect of each indicator. The result shows the best model is spatial error FEM in which education has the biggest influence compare than the others.
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Lasdiyanti, Mita, Eka N. Kencana, and Putu Suciptawati. "Modeling Human Development Index of Bali with Spatial Panel Data Regression." European Journal of Engineering and Technology Research 4, no. 5 (May 28, 2019): 132–37. http://dx.doi.org/10.24018/ejeng.2019.4.5.1312.
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Human development index (HDI) is an index that represents the successfulness of human development in a region. For Bali, one of 34 provinces in Indonesia, the progress of HDI in the period 2010–2017 showed an increasing trend. In the year 2010, the Bali’s HDI is accounted for 70.10, gradually increase to 74.30 in the year 2017. However, in 2017 there are some regions with their HDIs are below of Bali’s HDI, namely Jembrana, Buleleng, Klungkung, Bangli, and Karangasem. The aim of this work is to model the HDI of 9 regencies of Bali so that the main determinant to increase the HDIs especially for the regencies with lower HDIs could be determined. The model consists of one dependent variable (HDI) with three indicators as the independent ones, there are (a) life expectancy, (b) education, and (b) standard of living. By applying spatial panel data analysis, five models were built i.e. CEM, FEM (individual), FEM (time), REM, and spatial error FEM to determine the effect of each indicator. The result shows the best model is spatial error FEM in which education has the biggest influence compare than the others.
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Toomey, Ngoc, and Juan Carlos Ramos. "The Combination of Belinostat with Zidovudine for Treatment of HTLV-I Related Adult T-Cell Leukemia-Lymphoma." Blood 126, no. 23 (December 3, 2015): 1562. http://dx.doi.org/10.1182/blood.v126.23.1562.1562.
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Abstract Adult T-cell leukemia-lymphoma (ATLL) is an aggressive malignancy with poor prognosis that is incurable by conventional drugs. Histone deacetylase (HDAC) inhibitors (HDIs) are broadly active anti-neoplastic agents that can be cautiously exploited in the treatment of ATLL. The HTLV-I provirus is clonally integrated in virtually all ATLL cells. The HTLV-I 5'LTR promoter is trans -activated by the viral protein Tax through binding of CREB and p300/CBP. Tax binding enhances p300/CBP histone acetyl transferase (HAT) activity resulting in histone acetylation, chromatin unwinding, and transcription of the viral genome. HAT activity is countered by HDACs, and also by the viral-encoded protein HTLV-I bZip factor (HBZ), which is transcribed from the negative proviral strand at the 3' end. The 5' LTR is often mutated or deleted in ATLL cells thus HBZ is the only viral gene consistently expressed in ATLL. We hypothesized that HDAC inhibitors, which can be potent anti-neoplastic drugs, would reactivate HTLV-I in ATLL tumors containing intact provirus, thus killing virus-infected cells and provoking an immune response in vivo. Supporting this notion, adding the old generation HDI valproic acid (VPA) to AZT/IFNa in one subject suffering from aggressive acute-type ATLL resulted in HTLV-I proviral load reduction, followed by a complete molecular and prolonged clinical remission that lasted several years. We recently tested other more potent HDIs on primary ATLL cells and low-passage cell lines, which are rare and difficult to establish. In general, HDIs induced dose-dependent Tax expression and apoptosis in ATLL cells. Belinostat, a pan HDI, caused H3 acetylation, blocked HBZ protein expression, and induced Tax protein expression in ATLL cells resulting in concomitant apoptosis. ATLL cells exhibit high constitutive expression of nuclear factor kappa B (NF-kB), which is known to be activated by Tax and to play a major role in HTLV-I mediated T-cell transformation and ATLL development. Paradoxically, while belinostat induced Tax, it also inhibited NF-kB nuclear activity resulting in apoptosis. Further, adding AZT to belinostat augmented ATLL cell death. By contrast, IFNα diminished apoptosis induced by belinostat in freshly isolated ATLL cells from some of our patients. Based on these preclinical data, we have developed a clinical trial using belinostat in combination with AZT as consolidation therapy for ATLL. Our primary goal using this approach is to eradicate residual ATLL cells and HTLV-I infected reservoirs that normally persist regardless of treatment. Disclosures No relevant conflicts of interest to declare.
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shen, Tian, Helia Nasrollahi, Julia Taylor, Connie Tat, Hong Zan, and Paolo Casali. "Selective modulation of B cell mRNA and microRNA expression by histone deacetylase inhibitor (IRM10P.615)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 131.13. http://dx.doi.org/10.4049/jimmunol.194.supp.131.13.
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Abstract As we suggested, epigenetic factors such as miRNAs, can interact with genetic programs to regulate B cell functions and inform antibody response. We have shown that histone deacetylase inhibitors (HDIs) valproic acid and butyrate, inhibited class-switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation by modulating B cell intrinsic mechanisms. They repressed AID and Blimp-1 expression, which are critical for CSR/SHM and plasma cell differentiation, in mouse and human B cells by upregulating selected miRNAs that silenced AICDA/Aicda and PRDM1/Prdm-1 mRNAs, as demonstrated by qRT-PCRs. To further define the selectivity of HDI-mediated modulation of miRNA and gene expression, we performed miRNA-Seq and mRNA-Seq analysis in B cells stimulated with LPS plus IL-4 followed by VPA treatment. Consistent with our recent findings (J. Immunol. 193:5933-5950, 2014), these B cells showed reduced Aicda and Prdm1 expression, and increased expression of miR-155, miR-181b and miR-361, which target Aicda, and miR-23b, miR-30a and miR-125b, which target Prdm1,. The HDI-mediated modulation of mRNA was very selective. Among over 22,000 mRNAs analyzed, less than 20 mRNAs, including Aicda and Prdm1, significantly expressed in activated B cells were reduced by over two fold. Our findings indicate that, in B cells, HDI selectively modulate mRNAs, possibly through miRNA upregulation and as a result of HDACs existing in unique contexts of HDAC/co-factor complexes,.
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Dehm, Scott M., Traci L. Hilton, Edith H. Wang, and Keith Bonham. "SRC Proximal and Core Promoter Elements Dictate TAF1 Dependence and Transcriptional Repression by Histone Deacetylase Inhibitors." Molecular and Cellular Biology 24, no. 6 (March 15, 2004): 2296–307. http://dx.doi.org/10.1128/mcb.24.6.2296-2307.2004.
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ABSTRACT Histone deacetylase inhibitors (HDIs) induce cell cycle arrest, differentiation, or apoptosis in numerous cancer cell types both in vivo and in vitro. These dramatic effects are the result of a specific reprogramming of gene expression. However, the mechanism by which these agents activate the transcription of some genes, such as p21 WAF1 , but repress others, such as cyclin D1, is currently unknown. We have been studying the human SRC gene as a model for HDI-mediated transcriptional repression. We found previously that both the tissue-specific and housekeeping SRC promoters were equally repressed by HDIs. Here we show that, despite an overt dissimilarity, both SRC promoters do share similar core promoter elements and transcription is TAF1 dependent. Detailed analysis of the SRC promoters suggested that both core and proximal promoter elements were responsible for HDI-mediated repression. This was confirmed in a series of promoter-swapping experiments with the HDI-inducible, TAF1-independent p21 WAF1 promoter. Remarkably, all the SRC-p21 WAF1 chimeric promoter constructs were not only repressed by HDIs but also dependent on TAF1. Together these experiments suggest that the overall promoter architecture, rather than discrete response elements, is responsible for HDI-mediated repression, and they implicate core promoter elements in particular as potential mediators of this response.
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Chen, Jianguang, Veena Kandaswamy, Warren Fiskus, Yongchao Wang, Rekha Rao, Ramesh Balusu, Kathleen M. Buckley, Peter Atajada, and Kapil N. Bhalla. "Down-Regulation of Microrna 223 and 148a Mediates Resistance of Human Acute Myeloid Leukemia Cells to Pan-Histone Deacetylase (HDAC) Inhibitors." Blood 114, no. 22 (November 20, 2009): 2401. http://dx.doi.org/10.1182/blood.v114.22.2401.2401.
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Abstract Abstract 2401 Poster Board II-378 MicroRNA (miR) alterations are highly involved in the pathogenesis of leukemia. However, the role of miRs in de novo or acquired resistance of cancer cells to therapeutic agents has not been fully elucidated. Recently, we reported the isolation and characterization of HL-60/LR cells, derived from human acute myeloid leukemia HL-60 cells, that are resistant to pan-histone deacetylase (HDAC) inhibitors (HDIs), including vorinostat and panobinostat (Blood. 2008; 112: 2896). To explore the role of miRs in acquiring resistance to HDIs, we performed a miR microarray analysis of the parental HL-60 and HL-60/LR cells. Compared to HL-60 cells, expression of thirteen microRNAs were discovered to be significantly increased (> 4-fold) and fourteen miRs were markedly down-regulated (> 4-fold) in HL-60/LR cells. Alterations in the expression of three of the most promising upregulated (miR-21, miR-126 and miR-146a) and down-regulated (miR-223, miR-148a and miR-342) miRs were confirmed by Q-PCR in HL-60/LR cells. The expression of miR-223, miR-148a and miR-342 was also significant lower in the relatively HDI-resistant K562 cells as compared to HDI-sensitive U937 and HL-60 cells. Conversely, miR-126 and miR-146a expressions were higher in K562 cells compared to U937 and HL-60 cells. Short term (24 hours) treatment with panobinostat (10 to 50 nM) did not alter the expression of miR-223 or miR-148a expression in HL-60 cells. As compared to treatment with either agent alone, co-treatment with the histone methyl transferase EZH2 antagonist 3-deazaneplanocin (DZnep, 1.0 uM) and DNA methyl transferase inhibitor decitabine (2.0 uM) induced miR-223 and miR-148a levels and mediated apoptosis of HL-60/LR cells, suggesting that an epigenetic silencing mechanism(s) may be involved in the down-modulation of miR-223 and miR-148a in HL-60/LR cells. To determine whether the alterations in the miR levels were mechanistically involved in conferring resistance to HDIs, we engineered through retroviral transduction stable ectopic expressions of miR-223, miR-148a and miR-342 into HL-60/LR cells and miR-21 and miR-146a into HL-60 cells. Ectopic expression of miR-223 and miR-148a significantly increased the sensitivity of HL-60/LR cells to panobinostat and vorinostat. In contrast, re-expression of miR-342 had an insignificant effect on HDI sensitivity. Increased expression of miR-21 and miR-146a did not confer resistance to the HDIs in HL-60 and U937 cells. Next, by Western analyses, we compared the expression levels of several of the predicted target proteins of miR-223 and miR-148a, (as predicted by the computer programs TargetScan and picTAR), in HL-60 versus HL-60/LR cells, as well as in the HL-60/LR cells with stable ectopic expression of miR-223 and miR-148a. Several candidate proteins including GRP94, Ribosomal protein S6 kinase MSK1, MEF2C and DNMT1 showed higher level of expression in HL-60/LR versus HL-60 and were down-regulated in miR-223 or miR-148a transduced HL-60/LR cells, suggesting that these proteins may confer resistance against HDI. Parenthetically, miR-223 was shown to be a myeloid-specific miR which negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR-223 mutant mice have an expanded granulocytic compartment resulting from an increase in the number of granulocyte progenitors. In summary, our observations indicate that high miR-223 and miR-148a levels may be predictive biomarkers for sensitivity to HDIs in human AML cells. Additionally, induction of miR-223 and miR-148a by EZH2 antagonist may increase sensitivity and overcome resistance to HDIs in human AML cells. Targeting the levels and/or activity of the miR-223 and miR-148a target proteins may also be an effective strategy in enhancing the activity of HDI based combination therapy against AML. Disclosures: Atajada: Novartis: Employment. Bhalla:Merck: Honoraria; Novartis: Honoraria, Research Funding.
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Diaz, Ronald. "Effects of Pantawid Pamilyang Pilipino Program (4Ps) and other Conditional Cash Transfer (CCT) Programs of Low and Middle – Income Countries on Human Development." Sapienza: International Journal of Interdisciplinary Studies 2, no. 1 (March 30, 2021): 2–11. http://dx.doi.org/10.51798/sijis.v2i1.16.
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Despite the economic growth experienced by the Philippines in the recent years in terms of high GDP, poverty in the country still prevails. Prevalence of many poor families and individuals in the country prompted the Philippine government to implement the Pantawid Pamilyang Pilipino Program (Bridging Program for the Filipino Family) also known as 4Ps, the country’s conditional cash transfer (CCT) program that aims to provide conditional cash grants to the poorest of the poor. This paper aims to examine the effect of 4Ps on the country’s Human Development Index (HDI). It also seeks to find out if conditional cash transfer program provides significant effect on the HDIs of low and middle-income countries worldwide. The mean Human Development Index (HDI) of the Philippines before and throughout the implementation of 4Ps was compared. The difference between the HDIs of selected countries (low and middle-income) implementing and non-implementing the conditional cash transfer programs was determined. The findings of this study show that the Philippines has a significantly higher mean HDI during the implementation of 4Ps since 2008 to 2018 compared to its years when there was no 4Ps. The results further indicate that low and middle–income countries with CCT programs have significantly higher HDIs in comparison to their counterparts. A thorough evaluation of the CCT programs in terms of issues such as dependency and reviewing the conditionalities of the program to provide more significant and promising effect on HDI needs to be undertaken.
Keywords: Pantawid Pamilyang Pilipino Program (4Ps), conditional cash transfer (CCT), Human Development Index (HDI)
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Zhang, Xiu-lai, Meng Chen, Ling-ling Zhu, and Quan Zhou. "Therapeutic Risk and Benefits of Concomitantly Using Herbal Medicines and Conventional Medicines: From the Perspectives of Evidence Based on Randomized Controlled Trials and Clinical Risk Management." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–17. http://dx.doi.org/10.1155/2017/9296404.
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Despite increased awareness of the potential of herb-drug interactions (HDIs), the lack of rigorous clinical evidence regarding the significance provides a challenge for clinicians and consumers to make rational decisions about the safe combination of herbal and conventional medicines. This review addressed HDIs based on evidence from randomized controlled trials (RCTs). Literature was identified by performing a PubMed search till January 2017. Risk description and clinical risk management were described. Among 74 finally included RCTs, 17 RCTs (22.97%) simply addressed pharmacodynamic HDIs. Fifty-seven RCTs (77.03%) investigated pharmacokinetic HDIs and twenty-eight of them showed potential or actual clinical relevance. The extent of an HDI may be associated with the factors such as pharmacogenomics, dose of active ingredients in herbs, time course of interaction, characteristics of the object drugs (e.g., administration routes and pharmacokinetic profiles), modification of herbal prescription compositions, and coexistence of inducers and inhibitors. Clinical professionals should enhance risk management on HDIs such as increasing awareness of potential changes in therapeutic risk and benefits, inquiring patients about all currently used conventional medicines and herbal medicines and supplements, automatically detecting highly substantial significant HDI by computerized reminder system, selecting the alternatives, adjusting dose, reviewing the appropriateness of physician orders, educating patients to monitor for drug-interaction symptoms, and paying attention to follow-up visit and consultation.
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Decourtye-Espiard, Lyvianne, Nicola Bougen-Zhukov, Tanis Godwin, Tom Brew, Emily Schulpen, Michael A. Black, and Parry Guilford. "E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors." Cancers 14, no. 1 (December 30, 2021): 175. http://dx.doi.org/10.3390/cancers14010175.
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Inactivating germline mutations in the CDH1 gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic CDH1 mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking CDH1 expression. CDH1−/− breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. CDH1-null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both Cdh1 and Tp53 deletions. However, the deletion of Tp53 largely abrogated the sensitivity of the Cdh1-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1+/− murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic CDH1-deficient cancers.
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Li, Shun, Shanwu Lyu, Yujuan Liu, Ming Luo, Suhua Shi, and Shulin Deng. "Cauliflower mosaic virus P6 Dysfunctions Histone Deacetylase HD2C to Promote Virus Infection." Cells 10, no. 9 (September 1, 2021): 2278. http://dx.doi.org/10.3390/cells10092278.
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Histone deacetylases (HDACs) are vital epigenetic modifiers not only in regulating plant development but also in abiotic- and biotic-stress responses. Though to date, the functions of HD2C—an HD2-type HDAC—In plant development and abiotic stress have been intensively explored, its function in biotic stress remains unknown. In this study, we have identified HD2C as an interaction partner of the Cauliflower mosaic virus (CaMV) P6 protein. It functions as a positive regulator in defending against CaMV infection. The hd2c mutants show enhanced susceptibility to CaMV infection. In support, the accumulation of viral DNA, viral transcripts, and the deposition of histone acetylation on the viral minichromosomes are increased in hd2c mutants. P6 interferes with the interaction between HD2C and HDA6, and P6 overexpression lines have similar phenotypes with hd2c mutants. In further investigations, P6 overexpression lines, together with CaMV infection plants, are more sensitive to ABA and NaCl with a concomitant increasing expression of ABA/NaCl-regulated genes. Moreover, the global levels of histone acetylation are increased in P6 overexpression lines and CaMV infection plants. Collectively, our results suggest that P6 dysfunctions histone deacetylase HD2C by physical interaction to promote CaMV infection.
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Choi, Young Hee, and Young-Won Chin. "Multifaceted Factors Causing Conflicting Outcomes in Herb-Drug Interactions." Pharmaceutics 13, no. 1 (December 30, 2020): 43. http://dx.doi.org/10.3390/pharmaceutics13010043.
Full textAbstract:
Metabolic enzyme and/or transporter-mediated pharmacokinetic (PK) changes in a drug caused by concomitant herbal products have been a primary issue of herb and drug interactions (HDIs), because PK changes of a drug may result in the alternation of efficacy and toxicity. Studies on HDIs have been carried out by predictive in vitro and in vivo preclinical studies, and clinical trials. Nevertheless, the discrepancies between predictive data and the clinical significance on HDIs still exist, and different reports of HDIs add to rather than clarify the confusion regarding the use of herbal products and drug combinations. Here, we briefly review the underlying mechanisms causing PK-based HDIs, and more importantly summarize challenging issues, such as dose and treatment period effects, to be considered in study designs and interpretations of HDI evaluations.
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Guo, Fei, Celia Sigua, Purva Bali, Warren Fiskus, Gautam Sondarva, Srinivas Annavarapu, Abdelmoughite Mouttaki, Peter Atadja, and Kapil N. Bhalla. "Molecular Characterization of Human AML Cells with Resistance to Growth-Inhibitory and Apoptotic Effects of Hydroxamic Acid Analogue Histone Deacetylase Inhibitors." Blood 104, no. 11 (November 16, 2004): 1171. http://dx.doi.org/10.1182/blood.v104.11.1171.1171.
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Abstract The hydroxamic acid analogue (HA) class of histone deacetylase (HDAC) inhibitors (HDIs), e.g., SAHA, LAQ824 and LBH589, are active in inducing growth arrest and apoptosis of human acute and chronic leukemia cells. These agents have been shown to inhibit class I, IIA and IIB HDACs, induce histone H3 and H4 acetylation, increase p21 levels, as well as induce pro-death molecules Bax, Bak and Bim, while attenuating the levels of the antiapoptotic Bcl-xL, Bcl-2 and XIAP. Additionally, treatment with HA-HDIs have also been shown to induce acetylation of the heat shock protein (hsp) 90, thereby inhibiting its ATP binding and chaperone function, which directs the client proteins of hsp90 (e.g., AKT, c-Raf, FLT-3 and Bcr-Abl) to polyubiquitylation and proteasomal degradation. Collectively, these mechanisms explain the anti-leukemia activity of HA-HDIs. In the present studies, we cultured human AML HL-60 cells in the continuous presence of increasing levels of the cinnamic acid hydroxamate LAQ824, and isolated the HL-60/LR cells that are capable of growth in the continuous presence of 200 nM of LAQ824. HL-60/LR cells were 40 fold more resistant to the cell cycle growth inhibitory and apoptotic effects of LAQ824 than the parental control HL-60 cells, and showed variable degree of cross resistance to the other HA-HDIs, e.g., LBH589 (100 nM) and trichostatin A (250 nM), as well as to phenylbutyrate (3 mM). As compared to the control HL-60, HL-60/LR cells expressed markedly higher levels of Bcl-xL, XIAP, AKT and c-Raf, but lower levels of Bak and Bim. Exposure to 200 to 500 nM of LAQ824 for 24 hours induced histone acetylation in both HL-60 and HL-60/LR cells, suggesting that LAQ824 was able to inhibit HDAC activity in both cell types. However, as compared to HL-60, HL-60/LR cells expressed markedly lower HDAC6 but higher HDAC4 & 10 levels, while HDAC2 & 3 levels were similar in the two cell types. LAQ824-induced apoptosis was accompanied with the induction of p21, Bax and Bak and attenuation of Bcl-2, Bcl-xL and XIAP levels in the control HL-60 cells. This was not observed in HL-60/LR cells, which also demonstrated cross-resistance to apoptosis induced by Ara-C (0.5 to 2.0 μM for 48 hours) and TRAIL (100 to 500 ng/ml for 48 hours) but not to the topoisomerase II inhibitor etoposide (up to 2.0 μM). In contrast, HL-60/LR cells were collaterally more sensitive to the hsp90 inhibitor 17-allylamino-demothoxy geldanamycin (17-AAG) (Kosan Biosciences, Hayward, CA) (0.5 to 5.0 μM for 48 hours). These studies demonstrate that the in vitro resistance of HL-60/LR cells to HA-HDI LAQ824 is associated with perturbations in the levels of specific pro-survival and pro-death proteins. The cross resistance profile and the collateral sensitivity pattern of HL-60/LR cells points to 17-AAG and topoisomerase II inhibitor-based anti-leukemia combinations to override the de-novo or acquired resistance of AML cells to HA-HDIs.
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Kusideł, Ewa. "Convergence of Regional Human Development Indexes in Poland." Comparative Economic Research. Central and Eastern Europe 16, no. 1 (April 30, 2013): 87–102. http://dx.doi.org/10.2478/cer-2013-0006.
Full textAbstract:
The subject of convergence became popular in Poland upon its accession to the EU in 2004. Since then Poland has been a beneficiary of the cohesion policy – a regional policy of the European Union aimed at increasing the level of economic, social, and territorial (spatial) cohesion. While the economic aspect is a very thoroughly researched area of convergence studies, the social aspects are less often covered by specialist literature. This is the issue raised in this paper which, along with separate measures of social convergence, constructs a region HDI measure to evaluate the social cohesion of Poland’s regions1. Values of regional HDIs in Poland were not known and required calculation, which allowed for drawing conclusions about the standards of living of inhabitants in specific provinces. In general, it was possible to determine that HDIs are rising in all regions, which means, simultaneously, an increase in the standards of living of the provinces’ populations. At the same time, however, that growth was accompanied by increasing divergences in the HDI distribution among regions (sigma-divergence). The study of convergence of specific HDI components also allowed to note that HDI divergences are mainly caused by increasing economic inequalities between regions in Poland (measured by the Gross Domestic Product Index), and inequalities in education (measured by the Education Index).
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Mostofa, AGM, Allison Distler, Mark B. Meads, Eva Sahakian, John J. Powers, Tuan Nguyen, Melissa Alsina, et al. "Functional Analysis of HDAC11 in Plasma Cell Development and Multiple Myeloma Survival." Blood 132, Supplement 1 (November 29, 2018): 3223. http://dx.doi.org/10.1182/blood-2018-99-119119.
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Abstract Background: Histone deacetylases (HDACs) are potential novel therapeutic targets for multiple myeloma (MM) treatment. A pan-HDAC inhibitor (HDI) panobinostat was approved by the FDA in 2015 to treat relapsed/refractory MM patients, and several other HDIs are currently in different phases of clinical trials. However, unfavorable side-effects of the non-selective HDIs necessitate further dissection of the roles of individual HDAC isoforms to best target plasma cell malignancies with minimal toxicity. HDAC11 was recently found to regulate function in key immune cell populations including regulatory T cells, effector T cells, neutrophils, and myeloid-derived suppressor cells (MDSC). Though HDAC11 expression is confirmed in B cells and plasma cells, its functions in these cells remain largely unknown. In this study, we attempted a functional analysis of HDAC11 in plasma cell development along with its pro-tumorigenic function in MM cells. Methods: Mouse models, including a transgenic mouse strain expressing eGFP under the regulation of the HDAC11 promoter (Tg-HDAC11-eGFP), and also an HDA11-deficient mouse (B6.HDAC11-/-) were studied to establish the importance of HDAC11 in plasma cell biology. Pharmacologic inhibition of HDAC11 in MM cell lines was accomplished by using elevenostat, a new HDAC11-selective inhibitor in comparison with pan-inhibitors quisinostat and panobinostat. Impact on viability in human-derived MM cell lines was assessed using the CCK-8 assay, while induction of cell death was measured via detection of activated Caspase-3 and annexin/propidium iodide staining by flow cytometry. Synergy studies were performed by following the Chou-Talalay method for drug combinations. Post-translational modifications and subcellular localization changes induced by HDIs exposure were assessed by western blotting of fractionated cell lysates, while immunoprecipitation and proximity ligation assays (in situ PLA) were used to identify a binding partner for HDAC11. Results: Studies in Tg-HDAC11-eGFP mice reveal that HDAC11 expression in B cell lymphopoiesis is minimally detectable prior to B cell activation but demonstrates strong induction upon maturation into a plasma cell. Consistent with this, plasma cell development is markedly impaired in the absence of HDAC11. The HDAC11-selective inhibitor elevenostat showed significant cytotoxic potential in different MM cell lines that express moderate to high level of HDAC11, with IC50 values ranging 0.6-2.0 µM. Consistently, MM cell lines expressing null/very low level of HDAC11 were insensitive to elevenostat. Moreover, combining elevenostat with proteasome inhibitors bortezomib (BTZ) and carfilzomib resulted in significant synergistic effects evident from combination index (CI) and dose-reduction index (DRI) values measured by CompuSyn software. Elevenostat was also able to re-sensitize BTZ-resistant sub-clones (e.g., RPMI-8226-B25, KAS-6-V10R, and ANBL6-V10R) to BTZ and exhibited superior synergistic effects. Furthermore, elevenostat-treated cells showed a time-dependent alteration in the subcellular localization of HDAC11. HDAC11 gradually disappeared from the nuclear fractions with simultaneous upregulation in cytoplasmic fractions; similar observations were made from pan HDIs (quisinostat and panobinostat) treatment. However, unlike pan HDIs, the elevenostat treatment caused global downregulation of HDAC11 in some MM cell lines at the later time points (72 or 96 hrs), suggesting differential effects of various HDIs. Inhibition of HDAC11 also caused downstream suppression of several pro-tumorigenic factors of MM cells including IRF4 and c-Myc. Additionally, a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, was identified by using PLA. HDAC11 dynamically interacts with IRF4 which can be induced by LPS stimulation and inhibited by HDIs, indicating the involvement of HDAC11 in the IRF4-mediated regulatory circuit. Conclusions: We observe that targeted inhibition of HDAC11 can impair MM cell survival and overcome acquired resistance to proteasome inhibitors. Furthermore, we identify IRF4 as a nuclear binding partner of HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and survival. Disclosures No relevant conflicts of interest to declare.
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Fiskus, Warren, Rekha Rao, Pravina Fernandez, Bryan Herger, Yonghua Yang, Jianguang Chen, Yongchao Wang, et al. "Molecular Characterization and Drug-Sensitivity of Pan Histone Deacetylase Inhibitor Resistant Human Acute Myeloid Leukemia Cells." Blood 110, no. 11 (November 16, 2007): 807. http://dx.doi.org/10.1182/blood.v110.11.807.807.
Full textAbstract:
Abstract Hydroxamic acid analogue pan-histone deacetylase (HDAC) inhibitors (HA-HDIs), e.g., vorinostat, LAQ824 and LBH589, induce in vitro growth arrest, differentiation and apoptosis of human acute leukemia cells. Continuous and protracted use of HA-HDI, as currently used in the clinic against hematologic malignancies is likely to result in the emergence of HA-HDI resistance in leukemia cells. By continuous in vitro exposure of the AML HL-60 cells to the cinnamic acid analogue HA-HDI LAQ824, we have generated an in vitro and in vivo model of HA-HDI-resistant HL-60/LR cells, which are capable of growth in high concentrations (200 nM) of LAQ824. HL-60/LR versus the parental HL-60 cells have a shorter doubling time (12 versus 24 hours), increased % of cells in the S phase of the cell cycle (62.4 versus 40.0) and exhibit shorter interval to generation of leukemia and survival in NOD/SCID mice. As compared to HL-60, HL-60/LR cells have a resistance index of 100 for LAQ824, and are cross-resistant to other antileukemia agents exhibiting resistance index for LBH589: 50; trichostatin A: 15; vorinostat: 30; sodium butyrate: 10; etoposide: 5.0; Ara-C: 3.3 and TRAIL: 31.3. As compared to HL-60, HL-60/LR cells express higher levels of Bcl-xL and XIAP but lower levels of MCL-1. HL-60/LR versus HL-60 cells also express markedly reduced levels of Bim and Bak but higher levels of Bax. Although expressing higher levels of the death receptors (DR) 4 and 5 and lower levels of c-FLIP, HL-60/LR cells lack expression of caspase-8 and show barely detectable levels of FADD. Additionally, HL-60/LR versus HL-60 cells have markedly higher levels of AKT, c-RAF, and p-STAT5. Although expressing higher levels of HDAC1, HDAC2, and HDAC4, HL-60/LR cells lack detectable expression of HDAC6, with increased expression of hyper-acetylated hsp90 and α-tubulin- two of the substrates deacetylated by HDAC6. As compared to hsp90 in HL-60 cells, hyper-acetylated hsp90 in HL-60/LR cells exhibits less binding to ATP and p23. Utilizing a polyclonal antibody generated against acetylated hsp90α, confocal immunofluorescence microscopy showed higher and mostly cell surface expression of acetylated hsp90α in HL-60/LR versus HL-60 cells. As compared to HL-60, treatment of HL-60/LR cells with LAQ824 failed to induce p21 and hsp70, or increase the levels of hyper-acetylated hsp90 and α-tubulin. Notably, although cross-resistant to several anti-leukemia drugs, HL-60/LR cells are collaterally sensitive to the hsp90-inhibiting geldanamycin analogues 17-allylamino-demothoxy geldanamycin (17-AAG) and 17-DMAG with a four and five-fold increased sensitivity to 17-AAG and 17-DMAG, respectively. This was associated with a lack of both a 17-AAG mediated induction of hsp70 and a lesser decline in the levels of AKT and c-RAF in HL-60/LR versus HL-60 cells. Taken together, these findings elucidate several notable in vitro and in vivo biologic characteristics and drug-sensitivity profile of the first fully-characterized HA-HDI-resistant human AML cells. Our findings clearly demonstrate that in vitro resistance to HA-HDIs is associated with loss of HDAC6 expression, hyperacetylation of hsp90, aggressive leukemia phenotype, but cross-sensitivity to 17-AAG. These findings also suggest that hsp90 inhibitors should be tested for overriding de novo or acquired HA-HDI resistance in AML.
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Craddock, Charles, Charlotte Bradbury, Sujaatha Narayanan, Adam Rye, Supratik Basu, Alan MacWhannell, Alistair Sawers, et al. "Predictors of Clinical Response in Patients with High Risk Acute Myeloid Leukemia Receiving Treatment with the Histone Deacetylase Inhibitor Sodium Valproate." Blood 106, no. 11 (November 16, 2005): 2791. http://dx.doi.org/10.1182/blood.v106.11.2791.2791.
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Abstract There is increasing evidence that perturbations in chromatin structure contribute to the pathogenesis of AML raising the possibility that modulators of chromatin structure may be of therapeutic benefit. Sodium valproate (VPA) is a potent histone deacetylase inhibitor (HDI) and in conjunction with ATRA induces apoptosis of primary AML blasts in vitro. It has been postulated that induction of pro-apoptotic genes including p21 and TRAIL play a critical role in determining the tumor selectivity of HDIs. We have therefore conducted a Phase I/II study of combined VPA/ATRA therapy in patients with high risk AML ineligible for chemotherapy and correlated clinical response with alterations in chromatin structure, induction of pro-apoptotic genes and in vitro sensitivity to VPA. In light of evidence that modulating cAMP levels may increase rexinoid responsiveness theophylline was added in patients who had failed to respond to 28 days combined VPA/ATRA therapy. A total of 20 patients (median age 72 yrs) have been treated to date including 12 patients with relapsed AML, 6 with previously untreated disease and 2 with primary refractory disease. Nine patients completed treatment for at least 8 weeks. Four patients (all with relapsed AML) demonstrated a haematological response. One patient achieved a complete remission and two a partial remission. Myeloblasts isolated from trial patients prior to the commencement of therapy demonstrated varying sensitivity to VPA and ATRA in vitro which correlated with clinical response. Combined treatment with VPA and ATRA resulted in increased levels of histone acetylation and methylation and induced expression of p15, p16 and p21 in myeloblasts from treated patients. Induction of TRAIL was documented in three patients-two of whom demonstrated a clinical response. p21 induction was documented in all responding patients. Induction of p21 and TRAIL was most marked in the patient who achieved a CR. There was no apparent correlation between induction of p15 or p16 and response. We have previously documented that exposure of AML cell lines to HDIs results in specific changes in HDAC expression patterns with selective up-regulation of HDAC11 and to a lesser extent HDAC9 and SIRT4. Similar changes in HDAC expression were documented in myeloblasts from patients after 28 days treatment with VPA/ATRA. This study demonstrates that VPA, in combination with ATRA and theophylline, has significant clinical and biological activity and identifies possible mechanisms underlying the tumor-specific activity of VPA in AML in vivo.
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Freidkin, Ilya, Michal Herman, Ana Tobar, Avry Chagnac, Yaacov Ori, Asher Korzets, and Uzi Gafter. "Effects of histone deacetylase inhibitors on rat mesangial cells." American Journal of Physiology-Renal Physiology 298, no. 2 (February 2010): F426—F434. http://dx.doi.org/10.1152/ajprenal.00107.2009.
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Glomerular mesangial cells (MCs) proliferate and produce extracellular matrix proteins in many progressive renal diseases. Recently, histone deacetylase inhibitors (HDIs) were shown to have antiproliferative and antifibrogenic effects in some in vitro and in vivo models. Using the [3H]-thymidine incorporation test, we have found that the HDI trichostatin A (TSA) effectively inhibits MC growth at nontoxic nanomolar concentrations. Similarly, the HDI valproic acid also inhibited MCs proliferation. Cell-cycle analysis indicated an arrest in G0/G1 phase in response to TSA, which was accompanied by elevation in synthesis of the cyclin-dependent kinase inhibitors (CDKIs) p21/Waf1 and p27/Kip1. TSA treatment suppressed α-smooth muscle actin, transforming growth factor-β1, and collagen protein synthesis by MCs and induced myofibroblast-like appearance of proliferating MCs. In the in vivo model of the anti-Thy1.1-induced glomerulonephritis, TSA and valproic acid treatments significantly suppressed proteinuria. Collectively, these data suggest a therapeutic potential for HDIs in the treatment of mesangial proliferative diseases and glomerulosclerosis.
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Bogenberger, James M., Nanna Hansen, Devora Delman, Ruben A. Mesa, and Raoul Tibes. "MK2a Substrate-Selective p38 Inhibitor CMPD1 Selectively Synergizes with HDAC Inhibitors in CD34+ Cells from Myeloid Malignancies." Blood 124, no. 21 (December 6, 2014): 2239. http://dx.doi.org/10.1182/blood.v124.21.2239.2239.
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Abstract Background: Histone deacetylase (HDAC) inhibitors (HDIs) vorinostat (SAHA) and romidepsin are approved for the treatment of cutaneous T-cell lymphoma, while belinostat has recently been approved for the treatment of peripheral T-cell lymphoma. SAHA exhibits clinical activity in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), although insufficient to justify single-agent therapy for these indications. The precise clinical mechanism of SAHA and other HDIs remains incompletely characterized, impeding the design and implementation of rational HDI-based therapeutic combinations for myeloid malignancies. To circumvent this lack of mechanistic understanding, we conducted RNA-interference (RNAi) modifier screens of the kinome and phosphatome to identify signaling pathways that modulate SAHA (HDI) anti-leukemic activity in AML cell lines TF-1, HEL and THP-1 for rapid translation of findings from ex vivo validation to clinical application. Results: Multiple screen hits (both kinases and phosphatases) converge on distinct points of the p38-SAPK/JNK signaling pathways, suggesting involvement of these stress-activated pathways in SAHA anti-leukemic activity. However, the most well characterized p38α/β inhibitors SB202190 and LY2228820 do not augment SAHA anti-leukemic activity at any dose across the broad dose ranges tested. Similarly, the JNK inhibitor SP600125 does not modulate SAHA activity at doses that inhibit JNK. However, the putative MK2a substrate-selective p38 inhibitor CMPD1 (Boehringer-Ingelheim; Davidson, W., et. al., Biochemistry 2004 Sep 21;43(37):11658-71) selectively potentiates the activity of SAHA in all AML cell lines tested (N=8), as well as in ex vivo cultures of primary myeloid malignancies (N=14), including polycythemia vera, chronic myelomonocytic leukemia, MDS/myeloproliferative neoplasm overlap syndrome, MDS transformed to AML, and de novo AML. The observed dose-dependent synergy occurs at nanomolar doses consistent with the reported apparent inhibitory constant for CMPD1 inhibition of p38-dependent phosphorylation of MK2a. Further, SAHA + CMPD1 synergy is significantly greater in CD34+-selected as compared to CD34+-depleted cell populations ex vivo. Furthermore, CMPD1 is similarly synergistic with the HDI panobinostat in vitro, but interacts antagonistically with cytarabine and additively with 5-azacitidine. This suggests that CMPD1 interacts specifically with SAHA and panobinostat in AML. The synergistic interaction between CMPD1 and SAHA is independent of ROS induction, as pretreatment with N-acetylcysteine does not abrogate synergy, despite reducing single-agent SAHA activity. While CMPD1 is reported to be an MK2a substrate-selective p38 inhibitor, CMPD1 does not affect the regulation of several canonical MK2 targets at doses that are potently synergistic in AML cell lines, including the phosphorylation of HSP27 or AATF. To begin to probe the mechanism of CMPD1 and SAHA synergy more extensively, mRNA expression was measured by next-generation sequencing after SAHA and CMPD1 treatment alone and in combination in the AML cell line TF-1. Sequencing data is currently being analyzed and findings will be presented. Conclusion: RNAi knockdown of several p38-SAPK/JNK pathway components modulates SAHA activity in malignant myeloid cells; however, common pharmacological sensitizing targets remain elusive. We hypothesize that MK2 and/or a yet unrecognized pathway modulated by CMPD1 can be targeted for HDI combination therapy in malignant myeloid cells. Current and ongoing results from this study will provide validated targets for rational HDI combination in myeloid malignancies. Disclosures Off Label Use: LDE225/Sonidegib as investigational agent. Mesa:Incyte, CTI, NS pharma, Gilead, Celgene: Research Funding.
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Sundhani, Elza, Endang Lukitaningsih, Arief Nurrochmad, and Agung Endro Nugroho. "Potential pharmacokinetic and pharmacodynamic herb-drug interactions of Andrographis paniculata (Burm. f.) and andrographolide: A systematic review." Journal of Herbmed Pharmacology 11, no. 2 (April 1, 2022): 154–65. http://dx.doi.org/10.34172/jhp.2022.20.
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Introduction: Herb–drug interactions (HDIs) in pharmacokinetics and pharmacodynamics can occur when natural compounds are used in combination with drugs. This study aimed to review the potential interaction of Andrographis paniculata (Burm. f.) extract (APE) and its primary compound andrographolide (AND) with several drugs exhibiting various pharmacological activities.Methods: In this systematic review, articles were collected from international databases such as PubMed, Science Direct, Springer Link, and Scopus until August 2021. The following keywords were used: Andrographis paniculata, andrographolide, HDI, drug interaction, pharmacokinetics, and pharmacology. This review was written in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), SYRCLE’s risk of bias (RoB) tool for animal intervention studies, and Cochrane RoB 2 tool to analyze the RoB for qualitative assessment.Results: Twelve articles were included in accordance with the inclusion and exclusion criteria of this study. Five studies explored the potential of HDIs for combining APE with drugs and AND with theophylline, etoricoxib, nabumetone, naproxen, and tolbutamide. Five studies focused on AND in combination with aminophylline and doxofylline, meloxicam, glyburide, glimepiride, metformin, and warfarin. Two studies tested the combination of APE with gliclazide and midazolam. The HDI mechanism involving the inhibition or induction of cytochrome P450 enzyme expression was dominant in influencing the drug’s pharmacokinetic profile. Pharmacological studies on the combination of several drugs, particularly anti-inflammatory and antidiabetic drugs, showed a synergistic activity.Conclusion: APE and AND have potential pharmacokinetic and pharmacodynamic HDIs with various drugs. This study can be used as a therapeutic consideration in clinical aspects related to the possibility of HDIs of A. paniculata (Burm. f.).
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Gul, Hilal, Leah A. Marquez-Curtis, Jennifer Lo, Nadia Jahroudi, A. Robert Turner, Loree M. Larratt, and Anna Janowska-Wieczorek. "The Potent Deacetylase Inhibitor Trichostatin a (TSA) Increases CXCR4 Expression in Hematopoietic Stem/Progenitor Cells by Chromatin Remodelling." Blood 112, no. 11 (November 16, 2008): 3487. http://dx.doi.org/10.1182/blood.v112.11.3487.3487.
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Abstract Stromal-cell derived factor (SDF)-1α/CXCL12 and its cognate receptor, CXCR4, play a crucial role in the trafficking of normal hematopoietic stem/progenitor cells (HSPC) and their homing/retention in bone marrow. Consequently, modulation of CXCR4 expression in HSPC could be applied therapeutically to improve the efficiency of HSPC transplantation. It is known that gene expression can be regulated by chromatin remodelling. Two groups of histone modifying enzymes, histone acetyltransferase (HAT) and histone deacetylase (HDAC) participate in the regulation of chromatin structure, and hence gene expression. Disruption of normal HAT or HDAC activities has been found in many human cancers. Recently, several structurally diverse and highly specific HDAC inhibitors (HDI) have been reported. They act as strong modulators of growth, differentiation and apoptosis in several types of cancer, particularly acute myeloid leukemia (AML). However, very little is known regarding the effects of HDI on HSPC. We have previously shown that a specific short-chain fatty acid HDI, valproic acid (VPA), enhances CXCR4 expression and function in normal HSPC (Blood2007: 110; 425a). In order to determine whether other structurally diverse classes of HDI are able to influence CXCR4 expression in HSPC through chromatin remodelling, we investigated the effect of potent hydroxamic acid HDI Trichostatin A (TSA) on CXCR4 in normal HSPC. We examined the effect of TSA on CXCR4 expression (by FACS and real-time RT-PCR), modulation of CXCR4 transcription (chromatin immunoprecipitation (X-ChIP) analysis) and on functional response towards an SDF-1α gradient (by chemotaxis assay) of HSPC (CD34+ cells from cord blood (CB) and the models of immature hematopoietic cells expressing CD34 antigen, namely AML cell lines KG-1a and KG-1). Cells were incubated for 24 h in IMDM supplemented with 20% FCS in the presence of TSA (0.1 μM). We found that TSA increases the percentage of CXCR4-expressing CB CD34+, KG-1a, KG-1 cells (2.5-, 8- and 3-fold, respectively). This effect was also confirmed at the mRNA level in CB CD34+, KG-1a and KG-1 cells (by about 2.5-, 5- and 2.5-fold up-regulation, respectively). Moreover, X-ChIP analysis showed a significant increase in association of acetyl-histone H4 binding to the CXCR4 promoter in CB CD34+ and KG-1 cells (2- and 1.7-fold, respectively). TSA was also shown to significantly increase the chemotaxis of KG-1a cells towards SDF-1α (20 ng/mL), which was inhibited by AMD3100, a potent antagonist of CXCR4. We conclude that other HDI such as TSA regulate CXCR4 expression in HSPC by chromatin remodelling and we suggest that priming of HSPC with HDI may improve their homing and engraftment into bone marrow, especially in CB transplantation.
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Mkrtchyan, Gagik M., Tatiana O. Tagaeva, and Anastasia I. Boksler. "The Human Development Index under the Current Waste Management System in the Russian Regions." World of Economics and Management 19, no. 3 (2019): 41–57. http://dx.doi.org/10.25205/2542-0429-2019-19-3-41-57.
Full textAbstract:
This paper attempts to analyze the existing environmental issues in the Russian Federation with the help of macroeconomic indicators, with special emphases being placed on the Human Development Index (HDI). The work presents the algorithm of HDI calculation, examines its advantages and disadvantages and describes the possibility to reflect the environmental situation with the help of HDI. Scientific novelty of the study is the proposed method of computing HDI taking into account the situation in the field of waste management (earlier, macro indicators with environmental adjustment took into account only water and air pollution). Inclusion of waste accumulation parameter tends to decrease most regional HDIs in comparison with their traditional values, which underlines the gravity and relevance of waste challenges in the Russian Federation. The article highlights the shortcomings of the Russian environmental waste policy, and proposes the ways to stimulate the reduction of waste generation and accumulation.
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Eid Hassan, Eman Adel. "Evaluating the Trend of Trade between the Same Categories in the Human Development Index (HDI)." International Journal of Economics and Finance 14, no. 4 (March 15, 2022): 44. http://dx.doi.org/10.5539/ijef.v14n4p44.
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The first report of the human development index was at 1990, it is an important tool to evaluate the progress in the countries by GDP growth and social issues. Is the classification of HDII enough to explain the international relation between the categories of the countries that belongs to the same level of HDI? Giving evidences to grow the trend of trade between the nearest GDP countries, it is a formula of HDI and trade, the paper divided into three sections, First: The distribution of the human development index in the global and the areas that appeared; Second: Evaluate the distribution of the human development index in the top ten world; Third: Export between the top 10 HDI countries. Is really the full assessment of human development need a much broader set of indicators than the HDI alone? Can add the export rate to discuss the impact on the economic growth and the increasing on the income at the top ten countries at HDI? (Ranis, Stewart, & Samman, 2006).
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Khazaei, Salman, Shahab Rezaeian, Vali Baigi, Mohammad Saatchi, Leila Molaeipoor, and Zaher Khazaei. "Incidence and pattern of tuberculosis treatment success rates in different levels of the human development index: a global perspective." Southern African Journal of Infectious Diseases 32, no. 3 (October 1, 2017): 100–104. http://dx.doi.org/10.4102/sajid.v32i3.47.
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Background: Tuberculosis (TB) treatment success rate remains a public health challenge in many developed and developing countries. The correlation between the incidence and pattern of TB and the Human Development Index (HDI) has not been globally determined. This study aimed to determine the correlation between incidence and pattern of TB treatment success rates and HDI around the world.Methods: In this global perspective, we used data on incidence and treatment success rates of TB and HDI from the World Health Organisation (WHO) and World Bank, respectively.Results: The highest estimated incidence and lower treatment success rates of TB were restricted to countries with low HDIs. Life expectancy, education level, gross national income, HDI, and urbanisation were significantly associated with both TB incidence and treatment success rates.Conclusion: Patterns in TB incidence and treatment success rates are correlated with Human Development Indices. In addition to following WHO strategies, policy makers need to focus on the social and environmental determinants in order to reduce the TB burden, particularly in low income countries.
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Lipska, Katarzyna, Agata A. Filip, and Anna Gumieniczek. "Advances in studies on histone deactylase inhibitors as anticancer drugs." Postępy Higieny i Medycyny Doświadczalnej 72 (December 5, 2018): 1018–31. http://dx.doi.org/10.5604/01.3001.0012.7749.
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Inhibitors of histone deacetylases (HDIs), by affecting the process of histone acetylation, lead to changes in chromatin condensation, and in consequence, to changes in the expression of numerous genes responsible for the cell cycle and differentiation. Therefore, they can be effective in the treatment of cancer. The antitumor activity for over 15 HDIs has been confirmed so far, and some of them have been approved in the USA and Europe, mainly in combination with cytostatics or radiotherapy. For several HDIs, large clinical trials are being carried out to estimate their effectiveness, in monotherapy and new combinations. Other synthetic and natural compounds with HDI activity are tested in preclinical studies. HDIs differ in terms of chemical structure, biological activity and specificity in relation to individual HDACs. The compounds active against classic HDACs (Zn2+-dependent metalloproteins) are usually characterized by the presence the Zn2+ binding group, the linker part and the capping group. Taking into account the type of Zn2+ binding group, classic HDIs are classified as short-chain fatty acids, hydroxamic acids, cyclic peptides and benzamides. In turn, the nicotinamide adenine dinucleotide-dependent SIRTs inhibitors are small molecules, mostly nicotinamide and β-naphthol derivatives. The presented paper summarizes the most important information regarding the use of HDIs as anticancer drugs, regarding their diversified chemical structure, activity against HDACs, additional therapeutic properties and side effects. The review was made taking into account the literature from the last five years (2013-2017).
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Koyama, Yuki, So Pyay Thar, Chihiro Kizaki, Koki Toyota, Eiji Sawada, and Naruhito Abe. "Development of specific primers to Hirschmanniella spp. causing damage to lotus and their economic threshold level in Tokushima prefecture in Japan." Nematology 15, no. 7 (2013): 851–58. http://dx.doi.org/10.1163/15685411-00002723.
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Nematode diseases caused by Hirschmanniella spp. are becoming a major threat to lotus production in Tokushima Prefecture, a primary production area in Japan. The objectives of this study were: i) to design specific primers to Hirschmanniella spp. causing damage to lotus; ii) to evaluate the relationship between pre-plant density of Hirschmanniella spp. in soil and damage index of lotus; and iii) to establish an economic threshold level. Since two species, Hirschmanniella imamuri and H. diversa, are known as nematode pests on lotus, three real-time PCR primers were designed based on the ITS regions specific to H. imamuri (designated as imaF and imaR), H. diversa (divF and divR), and both species (HdiF and HdiR). The primers imaF and imaR did not react to DNA of nematodes extracted from lotus fields in Tokushima but the primers divF and divR did, suggesting that the damage seen in Tokushima is mainly caused by H. diversa. A calibration curve was made to evaluate the relationship between the number of Hirschmanniella spp. inoculated to soil and the threshold cycle values. The quantification of Hirschmanniella spp. in soil was conducted by real-time PCR method with the primers HdiF and HdiR as well as the Baermann method. The economic threshold level was estimated as ten individuals of Hirschmanniella spp. (100 g fresh soil)−1 with the Baermann method and 50 individuals (100 g oven-dried soil)−1 with real-time PCR.
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Morshneva, Alisa V., Olga O. Gnedina, Daria N. Kindt, and Maria V. Igotti. "Ras Participates in the Regulation of the Stability of Adenoviral Protein E1A via MAP-kinase ERK." Acta Naturae 14, no. 2 (July 21, 2022): 78–84. http://dx.doi.org/10.32607/actanaturae.11675.
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The E1A adenoviral protein required for the initiation of the viral life cycle is being actively studied as a sensitizing agent in the combination therapy of cancer, and tumors with activated Ras in particular. We investigated the role played by the Ras signaling pathway in the regulation of E1A protein stability and showed that overexpression of activated Ras increases the basal level of E1A, but enhances the degradation of the E1A protein under treatment with histone deacetylase inhibitors (HDIs). It has been found that the MAP kinase ERK is the key factor in E1A stabilization, and ERK inactivation upon HDI treatment reduces the E1A protein level. Our results indicate that the combination treatment of tumors with activated Ras using adenoviral E1A and HDI has limitations attributed to intense HDI-dependent degradation of E1A. Nevertheless, the established contribution of ERK kinase to the regulation of E1A stability can be used to search for new effective drug combinations based on the adenoviral E1A protein.
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Ouaissi, Mehdi, and Ali Ouaissi. "Histone Deacetylase Enzymes as Potential Drug Targets in Cancer and Parasitic Diseases." Journal of Biomedicine and Biotechnology 2006 (2006): 1–10. http://dx.doi.org/10.1155/jbb/2006/13474.
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The elucidation of the mechanisms of transcriptional activation and repression in eukaryotic cells has shed light on the important role of acetylation-deacetylation of histones mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Another group belonging to the large family of sirtuins (silent information regulators (SIRs)) has an (nicotinamide adenine dinucleotide)NAD+-dependent HDAC activity. Several inhibitors of HDACs (HDIs) have been shown to exert antitumor effects. Interestingly, some of the HDIs exerted a broad spectrum of antiprotozoal activity. The purpose of this review is to analyze some of the current data related to the deacetylase enzymes as a possible target for drug development in cancer and parasitic diseases with special reference to protozoan infections. Given the structural differences among members of this family of enzymes, development of specific inhibitors will not only allow selective therapeutic intervention, but may also provide a powerful tool for functional study of these enzymes.
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Fang, Zhi, Li-Xia Lou, and Ke Yao. "Socio-economic disparity in visual impairment from cataract." International Journal of Ophthalmology 14, no. 9 (September 18, 2021): 1310–14. http://dx.doi.org/10.18240/ijo.2021.09.03.
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AIM: To investigate the association of visual impairment from cataract with human development index (HDI) by years lived with disability (YLDs). METHODS: Published data on national age-standardized YLD rates caused by cataract and national HDIs in 2019 were obtained. Age-standardized YLD rates from 1990 to 2019 were analyzed to explore cataract burden among patients with different income levels. Age-standardized YLD rates in different HDI groups were compared by different degrees of visual impairment. Association between national age-standardized YLD rates and HDI in 2019 was analyzed. RESULTS: The age-standardized YLD rates of populations with visual impairment or blindness due to cataract declined from 1990 to 2019, especially among those with lower middle income. Multiple comparison tests revealed that countries with low HDI had significantly higher age-standardized YLD rates of blindness due to cataract than those with high and very high HDI (P<0.001). The age-standardized YLD rates of populations with blindness (β= -0.588, P<0.001), severe vision loss (β=-0.378, P<0.001), and moderate vision loss (β=-0.389, P<0.001) inversely correlated with HDI. CONCLUSION: Age-standardized YLD rates caused by cataract have declined since 1990. The burden of visual impairment due to cataract inversely correlate with national socioeconomic development and is more concentrated in countries with low HDI than those with high HDI, especially among the blind. These findings highlight the need to provide additional cataract services and cataract surgery coverage to developing countries to decrease the burden of avoidable blindness caused by cataract.
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C. Divakar, Madhu. "THE NEED FOR HERBOVIGILANCE." International Journal of Advanced Research 10, no. 11 (November 30, 2022): 34–44. http://dx.doi.org/10.21474/ijar01/15639.
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Objective: This communication outlines herbal drug safety, interactions between herbals and modern medicines, and factors that contribute to herb-drug interactions, including pharmacodynamic and pharmacokinetic interactions and their mechanisms. Methods: The study reviewed the various factors influencing the present pharmacovigilance system in comparison with the herbs related parameters, identified the advantages and disadvantage of the present system and derived modifications which are relevant to herbal drugs safety, efficacy and quality. Conclusion: The present pharmacovigilance system, being structured dominantlyfor modern medicines, needs to be reoriented to include detailed differences of herbal drugs with the former. Major limiting factors include suboptimal compilation of clinically relevant Herb-Drug interactions (HDIs), scarce reporting from patients and the failure to promptly recognized HDIs by health sector providers.A well-documented HDI-database prepared from appropriate case reports can detect ADR signals effectively.
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Bhalla, K. N., P. Bali, M. Balasis, W. Fiskus, M. Pranpat, K. Rocha, R. M. Rao, S. Kumaraswamy, and P. Atadja. "Inhibition of histone deacetylase (HDAC) 6 sensitizes human leukemia and breast cancer cells to antagonists of heat shock protein (hsp) 90 and/or bortezomib (BZ)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13039. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13039.
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13039 Background: HDAC6 is a cytosolic α-tubulin deacetylase, which shuttles misfolded polyubiquitylated proteins into aggresomes. Our studies demonstrated that the hydroxamic acid (HA) analogue pan-HDAC inhibitors (HDIs), e.g., LAQ824 and LBH589, induce α-tubulin and hsp90 acetylation, thereby inhibiting ATP-binding and chaperone function of hsp90. This promotes the polyubiquitylation and degradation of the pro-growth and pro-survival hsp90 client proteins, e.g., Bcr-Abl, mutant FLT-3, c-Raf and AKT in leukemia and Her-2 in breast cancer cells. Methods: Human CML K562 and breast cancer SKBR-3 and BT-474 cells were exposed to LAQ824 (100 nM) or LBH589 (20 to 50 nM) and/or 17-AAG (1 to 5 μM) and/or BZ (5 to 100 nM). K562 and BT-574 cells were also transfected with siRNA to HDAC6. Immunoprecipitation and/or immunoblot analysis were performed to determine the expression or binding of HDAC6 with hsp90, and of hsp90 acetylation and binding with its co-chaperones and client proteins. Immunofluorescent microscopy was utilized to estimate aggresome formation. Cellular cytotoxicity was determined by % inhibition of colony growth. Results: HDAC6 knockdown by its siRNA induced the acetylation of hsp90 and α-tubulin but not of the co-chaperones p23 and hsp40. HDAC6 binds to hsp90. Hsp90 acetylation increased its binding to biotinylated-geldanamycin (GM) and its analogue 17-AAG. Depletion of HDAC6 levels (∼70%) or its activity by treatment with HA-HDI also inhibited the binding of hsp90 to ATP, p23 and hsp90 client proteins, which was augmented by co-treatment with 17-AAG. Knockdown of HDAC6 sensitized the cells to loss of clonogenic survival induced by HA-HDI and/or BZ and/or 17-AAG. Depletion of HDAC6 led to attenuation of Her-2 levels and loss of survival of Her-2 amplified SKBR-3 and BT-474 cells. Co-localization of HDAC6 and polyubiquitylated proteins into aggresomes was enhanced by co-treatment with BZ and/or 17-AAG. This was inhibited by depletion of HDAC6 activity. Conclusions: These findings support the in vivo testing of HDAC6 inhibitors, which through inhibition of hsp90 and aggresome formation sensitizes cancer cells to 17-AAG and/or BZ induced cellular stress due to misfolded and polyubiquitylated proteins. [Table: see text]
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Zhou, Lihui, and John J. Puthenkalam. "Effects of the Human Development Index on COVID-19 Mortality Rates in High-Income Countries." European Journal of Development Studies 2, no. 3 (May 19, 2022): 26–31. http://dx.doi.org/10.24018/ejdevelop.2022.2.3.104.
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The coronavirus disease (COVID-19) pandemic has caused a huge loss of life and impaired public health worldwide. The finding that countries with high human development indices (HDIs) is associated with higher death rates during COVID-19 reported in earlier research is confusing. To clarify this significant problem, we explored the correlations and associations between the COVID-19 mortality rate and HDI based on updated data (until April 1, 2022) in 41 high-income countries across the world. The outcomes demonstrate: (a) a strong negative correlation between COVID-19 mortality rate and HDI; and (b) a significant (p = 0.013) negative association between COVID-19 mortality rate and HDI after controlling for health heterogeneities including aging population, full vaccination rate, GDP per capita, UHC, out-of-pocket burden, and stringency index. This paper concludes that reductions in the COVID-19 mortality rate depend to a great extent on the enhancement of human development capacity. Therefore, to better protect global public health, improving human development capacity should be a vital priority for all countries, whether in the present or in the future.
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Jopp, Tobias A. "Ein glücksökonomisch modifizierter Human Development Index für Deutschland (1920-1960)." Jahrbuch für Wirtschaftsgeschichte / Economic History Yearbook 58, no. 1 (May 24, 2017): 239–78. http://dx.doi.org/10.1515/jbwg-2017-0010.
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Abstract The United Nations’ Human Development Index (HDI) has become an important tool for measuring and comparing living standards between countries and regions. However, the HDI has also attracted a fair share of conceptual criticism. Starting from Andrea Wagner’s historical estimations of a HDI for Germany in the interwar and early postwar period, we take up part of that criticism by implementing three essential modifications to the mode of calculation. We test how far they alter our picture of the relative living standard in the Weimar Republic, the Third Reich, and the Federal Republic of Germany. First, we replace the arithmetic mean by the geometric mean, which is said to solve the problem of perfect substitutability; second, we extend the HDI by an additional fourth dimension measuring economic and political freedom – an important, though neglected, dimension; and third, as the perhaps most crucial conceptual intervention, we develop weighting schemes for the partial indices that are theoretically backed by happiness economic research. Thus, we challenge the common, but arbitrary fundamental assumption that all partial indices receive equal weights. Our results show that the HDI for Germany reacts very sensitively to conceptual interventions, making it difficult to use it for the intertemporal and international comparison of living standards. We also find that the proposed modified HDIs allow for a re-evaluation of the living standard in interwar Germany; and in contrast to what the reference estimations on the HDI for Germany say, there is a profound discontinuity between the Third Reich and post-war Germany in terms of living standards.
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Mansori, Kamyar, Erfan Ayubi, Fatemeh Khosravi Shadmani, Shiva Mansouri Hanis, Somayeh Khazaei, Mohadeseh Sani, Yousef Moradi, Salman Khazaei, and Abolfazl Mohammadbeigi. "Estimates of global HIV/AIDS mortality, prevalence and incidence rates, and their association with the Human Development Index." Biomedical Research and Therapy 4, no. 06 (June 25, 2017): 1399. http://dx.doi.org/10.15419/bmrat.v4i06.181.
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Background: HIV/AIDS is one of greatest global public health concerns today due to the high incidence, prevalence and mortality rates. The aim of this research was investigate and estimate the global HIV/AIDS mortality, prevalence and incidence rates, and explore their associations with the Human Development Index.
Methods: The global age-standardized rates of mortality, prevalence and incidence of HIV/AIDS were obtained from the UNAIDS for different countries in 2015. The human development indexes (HDIs) were obtained from the World Bank database. The surveyed countries were divided into four groups according to the HDI distribution. The Spearman correlation coefficient and one-way ANOVA test were used for assessing the association of HIV/ AIDS indicators and HDI.
Results: The highest rates of HIV/AIDS prevalence and incidence, and associated mortality in East and Southern Africa countries were 51.73%, 46.33% and 42.3%, respectively. Moreover, the highest and lowest global age-standardized rates of incidence and prevalence of HIV/AIDS was seen in adults ranging from 15-49 years of age for both low and high HDI countries. The prevalence and incidence rates of HIV/AIDS each had an inverse correlation with HDI and its four indicators (life expectancy at birth, mean years of schooling, expected years of schooling, and GNI per capita).
Conclusion: Less developed countries with lower HDI show greater severity of the AIDS epidemic. Thus, it is essential to pay more attention to HIV/AIDS control and prevention programs in these countries.
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Sheikh, Semira, Maria New, Mina Bekheet, Heidi Olzscha, and Nicholas B. La Thangue. "The TLR Adaptor Protein MyD88 Mediates Cell Sensitivity to HDAC Inhibitors through a Cytokine-Dependent Mechanism." Blood 128, no. 22 (December 2, 2016): 1766. http://dx.doi.org/10.1182/blood.v128.22.1766.1766.
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Abstract Introduction Histone deacetylase inhibitors (HDI) are promising new agents for the treatment of haematological malignancy including lymphoma. HDI have potent anti-proliferative effects in cell-based studies; in the clinical setting, however, the picture is quite variable, and the outcome of HDI therapy is complex and difficult to predict. The toll-like receptor (TLR) adaptor protein MyD88 (Myeloid Differentiation Primary Response Gene 88) is expressed at high levels in haematopoietic tissues and has recently been found to be the target for somatic mutation in lymphoid malignancies. In particular, substitution of the amino acid leucine to proline at position 265 (MyD88 L265P mutation) is estimated to be prevalent in over 90% of cases of Waldenstrom's macroglobulinaemia and around 37% of diffuse large B cell lymphoma (DLBCL) of the ABC subtype. Methods and Results Using an unbiased genome-wide loss-of-function screen (Fotheringham et al, 2009), MyD88 was identified as a key regulator and candidate biomarker which mediates the susceptibility of cancer cells to HDI: We show here in mechanism of action studies that expression of MyD88 can influence sensitivity of various cancer cell lines to treatment with an HDI. Short-term siRNA silencing of MyD88 reduced HDI sensitivity of U2OS osteosarcoma cells (as assessed by immunoblotting and FACS/propidium iodide staining), whereas over-expression of MyD88 and MyD88 L265P led to enhanced sensitivity. Given its role in TLR-signalling, we measured NFκB activity and pro-inflammatory cytokine expression, which were shown to be increased (in particular IL6 levels) when MyD88 was stably or transiently overexpressed in U2OS cells; co-expression of mutated MyD88 L265P augmented this effect. In DLBCL lymphoma cell lines of the ABC subtype, those cells expressing endogenous wild-type MyD88 (RIVA) were found to be less sensitive to HDI treatment compared to those cells carrying a heterozygous MyD88 L265P mutation (HBL-1). MyD88-mutated cells again showed higher levels of IL6 expression on cytokine analysis. Transient knockdown of endogenous MyD88 in ABC DLBCL cells resulted in decreased HDI sensitivity, as did disruption of the TLR/MyD88/NFκB signalling pathway by blocking either the TLR receptor, MyD88 aggregation or IL6 secretion. Immunohistochemical analysis of tumour tissue microarrays from patients with DLBCL carried out in conjunction with this work showed higher expression of MyD88 compared to patients with prostate or colorectal carcinoma. Finally, using a mass spectroscopy approach, we were able to show that MyD88 is acetylated, and that it can be directly deacetylated by the cytoplasmic histone deacetylase HDAC6. Discussion and translational significance Collectively our findings show that in cultured cells, high levels of MyD88 expression are associated with increased sensitivity to HDAC inhibition, whereas low level expression coincides with decreased sensitivity. We hypothesize that MyD88, in its role as adaptor protein in TLR signalling, plays an important role in regulating the expression and autocrine action of pro-inflammatory cytokines such as IL6 which contribute to the sensitization of cancer cells to HDI. The central role played by MyD88 in this mechanism highlights the importance of TLR signalling and innate immunity, and more generally the inflammatory properties of the extra-cellular tumour microenvironment in mediating the effects of HDAC inhibitors on malignant cells. Therefore, both expression level of MyD88 and MyD88 mutation status could serve as a potential biomarker for HDI sensitivity in patient selection. Disclosures No relevant conflicts of interest to declare.
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Lindoso, José Angelo L., and Ana Angélica B. P. Lindoso. "Neglected tropical diseases in Brazil." Revista do Instituto de Medicina Tropical de São Paulo 51, no. 5 (October 2009): 247–53. http://dx.doi.org/10.1590/s0036-46652009000500003.
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Poverty is intrinsically related to the incidence of Neglected Tropical Diseases (NTDs). The main countries that have the lowest human development indices (HDI) and the highest burdens of NTDs are located in tropical and subtropical regions of the world. Among these countries is Brazil, which is ranked 70th in HDI. Nine out of the ten NTDs established by the World Health Organization (WHO) are present in Brazil. Leishmaniasis, tuberculosis, dengue fever and leprosy are present over almost the entire Brazilian territory. More than 90% of malaria cases occur in the Northern region of the country, and lymphatic filariasis and onchocerciasis occur in outbreaks in a particular region. The North and Northeast regions of Brazil have the lowest HDIs and the highest rates of NTDs. These diseases are considered neglected because there is not important investment in projects for the development of new drugs and vaccines and existing programs to control these diseases are not sufficient. Another problem related to NTDs is co-infection with HIV, which favors the occurrence of severe clinical manifestations and therapeutic failure. In this article, we describe the status of the main NTDs currently occurring in Brazil and relate them to the HDI and poverty.
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Woodfield, Andrew, and Gérard Lemaitre. "Aerospace Titanium Alloy Melt Process Quality Improvements." MATEC Web of Conferences 321 (2020): 04008. http://dx.doi.org/10.1051/matecconf/202032104008.
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This Jet Engine Titanium Quality Committee (JETQC) paper describes industry quality improvements since 1990. Quality refers to freedom from melt-related hard-alpha and high-density inclusions (HDI). JETQC, formed under the auspices of the U.S. Federal Aviation Administration (FAA) following the Sioux City aircraft accident in 1989, is comprised of U.S., E.U. and Japanese aircraft engine manufacturers to address the quality of premium / rotor quality titanium alloy production. Titanium suppliers provide melt-related inclusion data. JETQC focuses on hard-alpha and HDI inclusion rates in premium quality (PQ) titanium alloy products for critical rotating aircraft engine applications. PQ materials typically are produced via triple vacuum arc re-melt (3XVAR) or hearth melt VAR (HMVAR) processes, but more recently, the Skull plus VAR (SVAR) process has been introduced. Hard-alpha rates have continued to decline over the last decade primarily for the HMVAR process. HDI rates declined in the early 90’s, but more recently the overall rate has stayed approximately constant with inclusions confined to the 3XVAR process. Combining the trends for both hard-alpha and HDIs, the HMVAR process has demonstrated in recent years to be higher quality compared with the 3XVAR process.
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Suh, Allison Y., Sung-Chang Lee, and Andreas A. Polycarpou. "Design Optimization of Ultra-Low Flying Head-Disk Interfaces Using an Improved Elastic-Plastic Rough Surface Model." Journal of Tribology 128, no. 4 (June 9, 2006): 801–10. http://dx.doi.org/10.1115/1.2345399.
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Sub-5nm flying head-disk interfaces (HDIs) designed to attain extremely high areal recording densities of the order of Tbit∕in2 are susceptible to strong adhesive forces, which can lead to subsequent contact, bouncing vibration, and high friction. Accurate prediction of the relevant interfacial forces can help ensure successful implementation of ultra-low flying HDIs. In this study, an improved rough surface model is developed to estimate the adhesive, contact, and friction forces as well as the mean contact pressure relevant to sub-5nm HDIs. The improved model was applied to four different HDIs of varying roughness and contact conditions, and was compared to the sub-boundary lubrication rough surface model. It was found that the interfacial forces in HDIs undergoing primarily elastic-plastic and plastic contact are more accurately predicted with the improved model, while under predominantly elastic contact conditions, the two models give similar results. The improved model was then used to systematically investigate the effect of roughness parameters on the interfacial forces and mean contact pressure (response). The trends in the responses were investigated via a series of regression models using a full 33 factorial design. It was found that the adhesive and net normal interfacial forces increase with increasing mean radius R of asperities when the mean separation is small (≈0.5nm), i.e., pseudo-contacting interface, but it increases primarily with increasing root-mean-square (rms) surface height roughness between 2 and 4nm, i.e., pseudo-flying interface. Also, increasing rms roughness and decreasing R, increases the contact force and mean contact pressure, while the same design decreases the friction force. As the directions of optimization for minimizing the individual interfacial forces are not the same, simultaneous optimization is required for a successful ultra-low flying HDI design.
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Sanchez, Helia N., Tian shen, Julia Renee Taylor, Kristina Munoz, Hong Zan, and Paolo Casali. "Short-chain fatty acid (SCFA) histone deacetylase inhibitors produced by gut microbiota regulate selected microRNAs to modulate local and systemic antibody responses." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 127.6. http://dx.doi.org/10.4049/jimmunol.196.supp.127.6.
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Abstract Epigenetic marks and factors, such as histone modifications and miRNAs, interact with genetic programs to regulate intrinsic B cell functions and inform antibody responses. As shown by our transcriptome and miRNome analyses, histone deacetylase inhibitors (HDIs) selectively downregulate AID, which is critical for class switch DNA recombination (CSR) and somatic hypermutation (SHM), and Blimp-1, the master transcription factor for B cells differentiation to plasma cells, by selectively upregulating miRNAs that target Aicda and Prdm1 mRNAs. As we have also shown, HDI-mediated impairment of CSR, SHM and plasma cell differentiation blunted T-dependent and T-independent antibody responses in wild type mice and autoantibody responses in lupus-prone mice. Potent HDI activity is displayed by butyrate and propionate, two abundant SCFA molecules generated by gut microbiota through fermentation of dietary fibers. We found that these SCFAs synergistically downregulate AID and Blimp-1 expression through selective miRNA upregulation. Feeding a no-fiber diet, or decreasing the load of SCFA-producing microbiota by treating mice with vancomycin reduced gut and serum SCFAs and resulted in increased IgA and IgG1 titers in serum and feces, and IgA+, IgG1+ B cells and plasma cells in Peyer’s patches, mesenteric lymph nodes and spleen. This outcome was reversed by administration of butyrate and propionate, which also synergistically inhibited CSR to IgG and IgA in purified human and mouse B cells in a dose-dependent fashion. Thus, endogenous HDIs integrate cues from metabolites by gut microbiota and relay them to selective downstream effectors, e.g. miRNAs, thereby modulating B cell differentiation and antibody/autoantibody responses.
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Thomas, Asha B., Durga C. Choudhary, Amol Raje, and Shatrughna S. Nagrik. "Pharmacokinetics and Pharmacodynamic Herb–Drug Interaction of Piperine with Atorvastatin in Rats." Journal of Chromatographic Science 59, no. 4 (January 13, 2021): 371–80. http://dx.doi.org/10.1093/chromsci/bmaa126.
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Abstract Herbals that are widely consumed as therapeutic alternatives to conventional drugs for cardiovascular diseases, may lead to herb–drug interactions (HDIs). Atorvastatin (ATR) is drug of choice for hyperlipidemia and is extensively metabolized through CYP3A4 enzyme. Thus, we postulate that concomitant administration of ATR with piperine (PIP, potent inhibitor of CYP3A4 enzyme)/ridayarishta (RID, cardiotonic herbal formulations containing PIP) may lead to potential HDI. A simple, accurate, sensitive high-performance liquid chromatography–photodiode array detection method using Kromasil-100 C18 column, mobile phase acetonitrile: 30 mM phosphate buffer (55:45 v/v) pH 4.5 with flow rate gradient programming was developed to study the potential HDI in rats. Method was found to be linear (2–100 ng/mL) with Lower Limit of Detection (LLOD) 2 ng/mL. The precision (%CV < 15%), accuracy (−1.0 to −10% R.E) with recoveries above 90% from rat plasma of ATR and IS were obtained. The pharmacokinetic (PK) interactions studies on co-administration of ATR (8.4 mg/kg, p.o.) with PIP (35 mg/kg, p.o.), demonstrated a threefold increase in Cmax of ATR (P < 0.01) with significant increase in AUC0–t/AUC0–∞ compared to ATR alone indicating potential PK-HDI. However co-administration of RID (4.2 mL/kg, p.o.) showed less significant changes (P > 0.05) indicating low HDI. The pharmacodynamic effects/interactions study (TritonX-100 induced hyperlipidemic model in rats) suggested no significant alterations in the lipid profile on co-administration of PIP/RID with ATR, indicating that there may be no significant pharmacodynamic interactions.
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shen, Tian, Helia Nasrollahi Sanchez, Hong Zan, and Paolo Casali. "Sirt1 modulates AID expression, class switch DNA recombination and somatic hypermutation by repressing NF-kB activity." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 198.11. http://dx.doi.org/10.4049/jimmunol.196.supp.198.11.
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Abstract As we have suggested, epigenetic factors, such as histone deacetylases (HDACs), play critical roles in modulating the maturation of the antibody response. This entails class switch DNA recombination (CSR) and somatic hypermutation (SHM). CSR and SHM require AID and diversify the specificity and effector functions of antibodies. By showing that HDAC inhibitors (HDIs) that selectively block Classes I/II HDACs (the “classical” Zn-dependent HDACs together with Class IV HDAC), impaired AID and Blimp1 expression, CSR, SHM and plasma cell differentiation, we have previously outlined an important role of these Zn-dependent HADCs in the modulation of antibody response. We found that Sirt1, one of the NAD+-dependent Class III HDACs or sirtuins (Sirts), played an important role in the regulation of CSR and SHM. Sirt1 deacetylated p65, an element of the canonical NF-kB pathway, which mediates AID induction, thereby repressing NF-kB activity. Sirt1 deficiency in B cells led to NF-kB hyperacetylation and activation, which resulted in enhanced AID expression and increased CSR to IgG, IgA and IgE. Conversely, Sirt1 deletion in AID expressing B cells of AicdacreSirt1fl/fl mice, whose B cells contain the normal complement of Aicda genes together with a Cre gene under control of an extra Aicda promoter, resulted in upregulated AID expression, increased CSR and SHM, and enhanced T-dependent and T-independent antibody response. These findings outline an important B cell-intrinsic role of Sirt1 in the modulation of the antibody response. Such a role is independent from and may be in addition to the histone deacetylation activity of this Class III HDAC. Supported by the NIH grants AI 105813, AI 079705 and ALR TIL grant ALR 295955.
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Cerchietti, Leandro, Maria E. Figueroa, David Meyers, Philip A. Cole, Kapil Bhalla, and Ari Melnick. "Connectivity Mapping of BCL6 Targeted Therapy Guides Rational Design of Potent and Specific Non-Chemotherapy Combinatorial Regimens in DLBCL." Blood 110, no. 11 (November 16, 2007): 523. http://dx.doi.org/10.1182/blood.v110.11.523.523.
Full textAbstract:
Abstract DLBCL is the most common form of non-Hodgkin’s lymphoma. Combinations of untargeted chemotherapeutic agents cure between 40–60% of DLBCL patients. We are interested in the rational design of targeted combinatorial therapy for DLBCL using non-chemotherapy agents. Towards this goal we developed an inhibitor of the BCL6 transcriptional repressor, the most commonly involved oncogene in DLBCL. This BCL6 peptide inhibitor (BPI) causes de-repression of BCL6 target genes and kills DLBCL cells. Since single agent targeted therapy is unlikely to cure tumors, we hypothesized that identification of survival pathways triggered by BPI would facilitate rational design of combinatorial biological therapy for DLBCL. In order to identify such pathways we performed gene expression (GE) microarray studies in ten DLCBL cell lines treated with BPI vs. control. Six cell lines were BCL6 positive and four were BCL6 negative. Only the BCL6 positive cells yielded differences in gene expression. Among BPI induced genes was the p300 histone acetyl-transferase. The overlapping genes among the six cell lines were used to generate a BPI response signature. We used this signature to query the Broad Institute Connectivity Map, which contains the GE signature of 164 distinct small-molecule perturbagens. The top scoring classes of drugs were the histone deacetylase inhibitors (HDIs) and HSP90 inhibitors. Considering that BPI is chemically un-related to HDIs or HSP90 inhibitors and that BPI induces p300, we hypothesized that a major biological effect of BPI is to cause the acetylation of HSP90 (which inhibits Hsp90 pro-survival activity) and p53, (which enhances its pro-apoptotic activity). We verified that p300 is a direct BCL6 target gene by ChIP assays, that BPI induces p300 mRNA and protein by QPCR and western blot, and that p300 is silenced in most primary DLBCLs at both the mRNA and protein levels. Accordingly, BPI induced acetylation of Hsp90 and inhibited its function, as demonstrated by the decrease in the abundance of Hsp90 client proteins (AKT/PKB and c-raf). BPI also induced acetylation and functional activity of p53 in a p300-dependent manner (and also induces p53 expression). The importance of p300 was confirmed since a p300-dominant negative construct and the specific p300(HAT) inhibitor Lys-CoA-TAT could block BPI antilymphoma activity. Remarkably, we observed a dose-sequence dependent synergistic effect of BPI followed by Hsp90 inhibitors in killing DLBCL cells. Hsp90 is a relevant target in DLBCL since HSP90?/? protein was expressed in ∼90% of DLBCL patients (n=70). HDIs also increase acetylation of Hsp90 and p53. The HDI drugs SAHA, valproic acid and TSA all profoundly synergized with BPI to specifically eradicate BCL6 positive DLBCL cell lines. In conclusion, we discovered an unexpected mechanistic link between BCL6 and suppression of protein acetylation in lymphomagenesis. This information was harnessed for the rational design of synergistic targeted therapy with BCL6 inhibitors followed by Hsp90 or HDAC inhibitors to target cellular pathways induced by BPI. We anticipate that these drug combinations will result in more potent and less toxic therapeutic treatment of DLBCL, possibly with less or no added chemotherapy.