Pharmacological targeting of bet bromodomain proteins in acute myeloid leukemia and malignant lymphomas : From molecular characterization to clinical applications

Altres ajuts: G.R. acknowledges supports from European Regional Development Fund (ERDF) "Una manera de hacer Europa".A25in25proarENG-pr910210011and DNA-protein interactions and abnormal chromatin remodeling are a major cause of uncontrolled gene transcription and constitutive activation of critical signaling pathways in cancer cells. Multiple epigenetic regulators are known to be deregulated in several hematologic neoplasms, by somatic mutation, amplification, or deletion, allowing the identification of specific epigenetic signatures, but at the same time providing new therapeutic opportunities. While these vulnerabilities have been traditionally addressed by hypomethylating agents or histone deacetylase inhibitors, pharmacological targeting of bromodomain-containing proteins has recently emerged as a promising approach in a number of lymphoid and myeloid malignancies. Indeed, preclinical and clinical studies highlight the relevance of targeting the bromodomain and extra-terminal (BET) family as an efficient strategy of target transcription irrespective of the presence of epigenetic mutations. Here we will summarize the main advances achieved in the last decade regarding the preclinical and clinical evaluation of BET bromodomain inhibitors in hematologic cancers, either as monotherapies or in combinations with standard and/or experimental agents. A mention will finally be given to the new concept of the protein degrader, and the perspective it holds for the design of bromodomain-based therapies

Recent advances in the targeting of epigenetic regulators in b-cell non-hodgkin lymphoma

In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field

Noncommutative generalizations of theorems of Cohen and Kaplansky

This paper investigates situations where a property of a ring can be tested on a set of "prime right ideals." Generalizing theorems of Cohen and Kaplansky, we show that every right ideal of a ring is finitely generated (resp. principal) iff every "prime right ideal" is finitely generated (resp. principal), where the phrase "prime right ideal" can be interpreted in one of many different ways. We also use our methods to show that other properties can be tested on special sets of right ideals, such as the right artinian property and various homological properties. Applying these methods, we prove the following noncommutative generalization of a result of Kaplansky: a (left and right) noetherian ring is a principal right ideal ring iff all of its maximal right ideals are principal. A counterexample shows that the left noetherian hypothesis cannot be dropped. Finally, we compare our results to earlier generalizations of Cohen's and Kaplansky's theorems in the literature.Comment: 41 pages. To appear in Algebras and Representation Theory. Minor changes were made to the numbering system, in order to remain consistent with the published versio

Native Variants of the MRB1 Complex Exhibit Specialized Functions in Kinetoplastid RNA Editing

We want to thank Kathy Kyler for editing this manuscript, Ken Stuart for supplying monoclonal antisera against RECC subunits, and Laurie K. Read for her gift of polyclonal antisera against GAP1 and RGG2. Funding: National Science Foundation Grant No. NSF1122109 (PI: J.Cruz-Reyes.). NIH/National Institute of Allergies and Infectious Diseases R01 AI088011 (PI: Blaine Mooers). Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103640. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Adaptation and survival of Trypanosoma brucei requires editing of mitochondrial mRNA by uridylate (U) insertion and deletion. Hundreds of small guide RNAs (gRNAs) direct the mRNA editing at over 3,000 sites. RNA editing is controlled during the life cycle but the regulation of substrate and stage specificity remains unknown. Editing progresses in the 3’ to 5’ direction along the pre-mRNA in blocks, each targeted by a unique gRNA. A critical editing factor is the mitochondrial RNA binding complex 1 (MRB1) that binds gRNA and transiently interacts with the catalytic RNA editing core complex (RECC). MRB1 is a large and dynamic complex that appears to be comprised of distinct but related subcomplexes (termed here MRBs). MRBs seem to share a ‘core’ complex of proteins but differ in the composition of the ‘variable’ proteins. Since some proteins associate transiently the MRBs remain imprecisely defined. MRB1 controls editing by unknown mechanisms, and the functional relevance of the different MRBs is unclear. We previously identified two distinct MRBs, and showed that they carry mRNAs that undergo editing. We proposed that editing takes place in the MRBs because MRBs stably associate with mRNA and gRNA but only transiently interact with RECC, which is RNA free. Here, we identify the first specialized functions in MRBs: 1) 3010-MRB is a major scaffold for RNA editing, and 2) REH2-MRB contains a critical trans-acting RNA helicase (REH2) that affects multiple steps of editing function in 3010-MRB. These trans effects of the REH2 include loading of unedited mRNA and editing in the first block and in subsequent blocks as editing progresses. REH2 binds its own MRB via RNA, and conserved domains in REH2 were critical for REH2 to associate with the RNA and protein components of its MRB. Importantly, REH2 associates with a ~30 kDa RNA-binding protein in a novel ~15S subcomplex in RNA-depleted mitochondria. We use these new results to update our model of MRB function and organization.Yeshttp://www.plosone.org/static/editorial#pee

Anticoagulant therapy for splanchnic vein thrombosis: an individual patient data meta-analysis

Robust evidence on the optimal management of splanchnic vein thrombosis (SVT) is lacking. We conducted an individual-patient meta-analysis to evaluate the effectiveness and safety of anticoagulation for SVT. Medline, Embase, and clincaltrials.gov were searched up to June 2021 for prospective cohorts or randomized clinical trials including patients with SVT. Data from individual datasets were merged, and any discrepancy with published data was resolved by contacting study authors. Three studies of a total of 1635 patients were included. Eighty-five percent of patients received anticoagulation for a median duration of 316 days (range, 1-730 days). Overall, incidence rates for recurrent venous thromboembolism (VTE), major bleeding, and mortality were 5.3 per 100 patient-years (p-y; 95% confidence interval [CI], 5.1-5.5), 4.4 per 100 p-y (95% CI, 4.2-4.6), and 13.0 per 100 p-y (95% CI, 12.4-13.6), respectively. The incidence rates of all outcomes were lower during anticoagulation and higher after treatment discontinuation or when anticoagulation was not administered. In multivariable analysis, anticoagulant treatment appeared to be associated with a lower risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.27-0.64), major bleeding (HR, 0.47; 95% CI, 0.30-0.74), and mortality (HR, 0.23; 95% CI, 0.17-0.31). Results were consistent in patients with cirrhosis, solid cancers, myeloproliferative neoplasms, unprovoked SVT, and SVT associated with transient or persistent nonmalignant risk factors. In patients with SVT, the risk of recurrent VTE and major bleeding is substantial. Anticoagulant treatment is associated with reduced risk of both outcomes. © 2022 by The American Society of Hematology

Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'.

Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required

New prioritized value iteration for Markov decision processes

The problem of solving large Markov decision processes accurately and quickly is challenging. Since the computational effort incurred is considerable, current research focuses on finding superior acceleration techniques. For instance, the convergence properties of current solution methods depend, to a great extent, on the order of backup operations. On one hand, algorithms such as topological sorting are able to find good orderings but their overhead is usually high. On the other hand, shortest path methods, such as Dijkstra's algorithm which is based on priority queues, have been applied successfully to the solution of deterministic shortest-path Markov decision processes. Here, we propose an improved value iteration algorithm based on Dijkstra's algorithm for solving shortest path Markov decision processes. The experimental results on a stochastic shortest-path problem show the feasibility of our approach. © Springer Science+Business Media B.V. 2011.García Hernández, MDG.; Ruiz Pinales, J.; Onaindia De La Rivaherrera, E.; Aviña Cervantes, JG.; Ledesma Orozco, S.; Alvarado Mendez, E.; Reyes Ballesteros, A. (2012). New prioritized value iteration for Markov decision processes. Artificial Intelligence Review. 37(2):157-167. doi:10.1007/s10462-011-9224-zS157167372Agrawal S, Roth D (2002) Learning a sparse representation for object detection. In: Proceedings of the 7th European conference on computer vision. Copenhagen, Denmark, pp 1–15Bellman RE (1954) The theory of dynamic programming. Bull Amer Math Soc 60: 503–516Bellman RE (1957) Dynamic programming. Princeton University Press, New JerseyBertsekas DP (1995) Dynamic programming and optimal control. Athena Scientific, MassachusettsBhuma K, Goldsmith J (2003) Bidirectional LAO* algorithm. In: Proceedings of indian international conferences on artificial intelligence. p 980–992Blackwell D (1965) Discounted dynamic programming. Ann Math Stat 36: 226–235Bonet B, Geffner H (2003a) Faster heuristic search algorithms for planning with uncertainty and full feedback. In: Proceedings of the 18th international joint conference on artificial intelligence. Morgan Kaufmann, Acapulco, México, pp 1233–1238Bonet B, Geffner H (2003b) Labeled RTDP: improving the convergence of real-time dynamic programming. In: Proceedings of the international conference on automated planning and scheduling. Trento, Italy, pp 12–21Bonet B, Geffner H (2006) Learning depth-first search: a unified approach to heuristic search in deterministic and non-deterministic settings and its application to MDP. In: Proceedings of the 16th international conference on automated planning and scheduling. Cumbria, UKBoutilier C, Dean T, Hanks S (1999) Decision-theoretic planning: structural assumptions and computational leverage. J Artif Intell Res 11: 1–94Chang I, Soo H (2007) Simulation-based algorithms for Markov decision processes Communications and control engineering. Springer, LondonDai P, Goldsmith J (2007a) Faster dynamic programming for Markov decision processes. Technical report. Doctoral consortium, department of computer science and engineering. University of WashingtonDai P, Goldsmith J (2007b) Topological value iteration algorithm for Markov decision processes. In: Proceedings of the 20th international joint conference on artificial intelligence. Hyderabad, India, pp 1860–1865Dai P, Hansen EA (2007c) Prioritizing bellman backups without a priority queue. In: Proceedings of the 17th international conference on automated planning and scheduling, association for the advancement of artificial intelligence. Rhode Island, USA, pp 113–119Dibangoye JS, Chaib-draa B, Mouaddib A (2008) A Novel prioritization technique for solving Markov decision processes. In: Proceedings of the 21st international FLAIRS (The Florida Artificial Intelligence Research Society) conference, association for the advancement of artificial intelligence. Florida, USAFerguson D, Stentz A (2004) Focused propagation of MDPs for path planning. In: Proceedings of the 16th IEEE international conference on tools with artificial intelligence. pp 310–317Hansen EA, Zilberstein S (2001) LAO: a heuristic search algorithm that finds solutions with loops. Artif Intell 129: 35–62Hinderer K, Waldmann KH (2003) The critical discount factor for finite Markovian decision processes with an absorbing set. Math Methods Oper Res 57: 1–19Li L (2009) A unifying framework for computational reinforcement learning theory. PhD Thesis. The state university of New Jersey, New Brunswick. NJLittman ML, Dean TL, Kaelbling LP (1995) On the complexity of solving Markov decision problems.In: Proceedings of the 11th international conference on uncertainty in artificial intelligence. Montreal, Quebec pp 394–402McMahan HB, Gordon G (2005a) Fast exact planning in Markov decision processes. In: Proceedings of the 15th international conference on automated planning and scheduling. Monterey, CA, USAMcMahan HB, Gordon G (2005b) Generalizing Dijkstra’s algorithm and gaussian elimination for solving MDPs. Technical report, Carnegie Mellon University, PittsburghMeuleau N, Brafman R, Benazera E (2006) Stochastic over-subscription planning using hierarchies of MDPs. In: Proceedings of the 16th international conference on automated planning and scheduling. Cumbria, UK, pp 121–130Moore A, Atkeson C (1993) Prioritized sweeping: reinforcement learning with less data and less real time. Mach Learn 13: 103–130Puterman ML (1994) Markov decision processes. 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Maslinic Acid, a Natural Triterpene, Induces a Death Receptor-Mediated Apoptotic Mechanism in Caco-2 p53-Deficient Colon Adenocarcinoma Cells

Maslinic acid (MA) is a natural triterpene present in high concentrations in the waxy skin of olives. We have previously reported that MA induces apoptotic cell death via the mitochondrial apoptotic pathway in HT29 colon cancer cells. Here, we show that MA induces apoptosis in Caco-2 colon cancer cells via the extrinsic apoptotic pathway in a dose-dependent manner. MA triggered a series of effects associated with apoptosis, including the cleavage of caspases -8 and -3, and increased the levels of t-Bid within a few hours of its addition to the culture medium. MA had no effect on the expression of the Bax protein, release of cytochrome-c or on the mitochondrial membrane potential. This suggests that MA triggered the extrinsic apoptotic pathway in this cell type, as opposed to the intrinsic pathway found in the HT29 colon-cancer cell line. Our results suggest that the apoptotic mechanism induced in Caco-2 may be different from that found in HT29 colon-cancer cells, and that in Caco-2 cells MA seems to work independently of p53. Natural antitumoral agents capable of activating both the extrinsic and intrinsic apoptotic pathways could be of great use in treating colon-cancer of whatever origin.This study was supported by grants Group BIO 157 from the Technology and Innovation Council of the Andalucian regional government and AGL2006-12210-C03-02/ALI, SAF2005-01627, ISCIII-RTICC (RD06/0020/0046) from the Spanish government and European Union FEDER funds

Lysine-91 of the tetraheme c-type cytochrome CymA is essential for quinone interaction and arsenate respiration in Shewanella sp. strain ANA-3

The tetraheme c-type cytochrome, CymA, is essential for arsenate respiratory reduction in Shewanella sp. ANA-3, a model arsenate reducer. CymA is predicted to mediate electron transfer from quinols to the arsenate respiratory reductase (ArrAB). Here, we present biochemical and physiological evidence that CymA interacts with menaquinol (MQH2) substrates. Fluorescence quench titration with the MQH2 analog, 2-n-heptyl-4-hydroxyquinoline-N-oxide (HOQNO), was used to demonstrate quinol binding of E. coli cytoplasmic membranes enriched with various forms of CymA. Wild-type CymA bound HOQNO with a Kd of 0.1–1 μM. It was also shown that the redox active MQH2 analog, 2,3-dimethoxy-1,4-naphthoquinone (DMNH2), could reduce CymA in cytoplasmic membrane preparations. Based on a CymA homology model made from the NrfH tetraheme cytochrome structure, it was predicted that Lys91 would be involved in CymA-quinol interactions. CymA with a K91Q substitution showed little interaction with HOQNO. In addition, DMNH2-dependent reduction of CymA-K91Q was diminished by 45% compared to wild-type CymA. A ΔcymA ANA-3 strain containing a plasmid copy of cymA-K91Q failed to grow with arsenate as an electron acceptor. These results suggest that Lys91 is physiologically important for arsenate respiration and support the hypothesis that CymA interacts with menaquinol resulting in the reduction of the cytochrome

Operationalizing local ecological knowledge in climate change research : challenges and opportunities of citizen science

Current research on the local impacts of climate change is based on contrasting results from the simulation of historical trends in climatic variables produced with global models against climate data from independent observations. To date, these observations have mostly consisted of weather data from standardized meteorological stations. Given that the spatial distribution of weather stations is patchy, climate scientists have called for the exploration of new data sources. Knowledge developed by Indigenous Peoples and local communities with a long history of interaction with their environment has been proposed as a data source with untapped potential to contribute to our understanding of the local impacts of climate change. In this chapter, we discuss an approach that aims to bring insights from local knowledge systems to climate change research. First, we present a number of theoretical arguments that give support to the idea that local knowledge systems can contribute in original ways to the endeavors of climate change research. Then, we explore the potential of using information and communication technologies to gather and share local knowledge of climate change impacts. We do so through the examination of a citizen science initiative aiming to collect local indicators of climate change impacts: the LICCI project (www.licci.eu). Our findings illustrate that citizen science can inspire new approaches to articulate the inclusion of local knowledge systems in climate change research. However, this requires outlining careful approaches, with high ethical standards, toward knowledge validation and recognizing that there are aspects of local ecological knowledge that are incommensurable with scientific knowledge