1,720,985 research outputs found
From epigenetics to lipid metabolism: different approaches to fight cancer
Full text linkDuring my Phd I have been working on the developement of small molecules as modulators of epigenetic and non-epigenetic targets involved in cancer development ad progression. Mainly my work have been focused on the development of inhibitors (dimethylpyridone containing pyrrole- and pyrazole-based) of the lysine methyltransferase EZH2 as the catalytically active member of the Polycomb complex PRC2. These studies yielded the identification of novel EZH2is, also revealing nice SAR data. Some of the novel compounds showed promising activity in cancer cells having antiproliferative effects, reducing the H3K27 methylation, inducing apoptosis and autophagy. One of the novel compounds proved active also in a mouse model of medulloblastoma. Additionally, a Medicinal Chemistry study on Astemizole, as potential PRC2 disruptor, have been performed. For this project no biological data are jet available. In addition, a guest research stay at the University of Oxford (with S. Conway) resulted in a study on the design, synthesis and preliminary assays of photoaffinity probes for BET bromodomains. Finally, I worked on a new target from the field of lipid signalling, alkylglycerone phosphate synthase (AGPS) by developing SAR studied on the first in class AGPS inhibitor published in 2015 by the group of Prof. Mai
Full system emulation of approximate memory platforms with AppropinQuo
Full text linkIn this work we present an emulation framework for hardware platforms provided with approximate memory units, called AppropinQuo. The specific characteristic of AppropinQuo is to reveal the effects, on the hardware platform and on software, of errors introduced by approximate memory circuits and architectures. The emulator allows to execute software code without any modification with respect to the target physical board, since it includes the CPU, the memory hierarchy and the peripherals, capturing as well software-hardware interactions and faults due to approximate memory units. The final scope is reproducing the effects of errors generated by approximate memory circuits, allowing to evaluate the impact (quality degradation) on the output produced by the software. In fact, output quality is related to error rate, but their relationship strongly depends on the application, the implementation and its data representation on physical memory. The idea behind approximate memory circuits and approximate computing in general is to trade off energy consumption at the expense of computational accuracy and degradation of output quality. Memory is accounted for a large part of total power consumption in advanced architectures and it is supposed to increase as new memory hungry applications migrate toward the implementation on embedded systems (embedded machine learning, high definition video codecs, etc.). By relaxing design constraints regarding error probability on bit cells, researchers have proposed techniques that significantly reduce memory energy consumption. These techniques, which can be accounted in the general topic of approximate memory design, are implemented at circuit or architecture level, and are specific to the memory technology (i.e., SRAM or DRAM memories). However, the level of acceptable output degradation is the final metric that must be used to assess if, and to what extent, an approximate memory technique can be introduced. Our emulator allows to run actual applications as on the physical platform, to expose the effects of specific approximate memory circuits and architectures on output quality and to vary their parameters (e.g., error rate, number of affected bits, etc.). By exploring the approximate memory design space and its effects on the output of a software application, it is possible to characterize the application behavior, as a step toward the determination of the trade-off between saved energy and output quality (energy-quality tradeoff)
LSD1 inhibitors: a patent review (2010-2015)
No full textIntroduction: Lysine demethylase 1 (LSD1) plays an important role in mediating the expression of genes involved in cancer and non-cancer diseases such as viral infections, cardiovascular and neurodegenerative disorders. It is involved in a number of processes from adipogenesis to cell adhesion to viral latency, regulating several cell pathways related with proliferation, development, and cell cycle control. Numerous chemical entities have been studied in recent years and some of them entered the clinical arena.
Areas covered: This review summarizes recent efforts in the drug development of LSD1 inhibitors reported in the patent literature covering the 2010-2015 period, including their potential use as therapeutics in cancerous, neurological, inflammatory, cardiovascular, and viral diseases.
Expert opinion: The development of novel potent and selective LSD1 inhibitors is ongoing, in order to improve their potency and selectivity against specific types of cancer or non-cancer diseases. More in-depth studies are required to assess the role of LSD1 inhibitors in the expression of LSD1 target genes, for a better assessment of the biochemistry underlying their efficacy, and to provide evidence for any possible side effects. Furthermore, an interesting therapeutic approach is the use of LSD1 inhibitors in conjunction with other epidrugs to combine their therapeutic potential, leading to innovative, personalized treatments
An emulator for approximate memory platforms based on QEmu
No full textIn this paper, an emulation environment for approximate memory architectures is presented. In the context of error tolerant applications, in which energy is saved at the expense of the occurrence of errors in data processing, approximate memories play a relevant part. Approximate memories are memories where read/write errors are allowed with controlled probability. In general these errors are the result of circuital or architectural techniques (i.e. voltage scaling, refresh rate reduction) introduced to save energy. The ability to simulate these systems is particularly important since the amount of tolerated error is application dependent. Simulation allows to analyze the behavior of an application and explore its tolerance to actual error rates, determining the trade-off between saved energy and output quality. We have developed an emulation environment for such architectures, based on QEmu, which allows the execution of programs that can allocate some of their data in a memory zone subject to faults.We present the emulated architecture, the fault injection model and a case of study showing results that can be obtained by our emulator
Introducing approximate memory support in Linux Kernel
No full textThis paper describes the implementation of approximate memory support in Linux operating system kernel. The new functionality allows the kernel to distinguish between normal memory banks, which are composed by standard memory cells that retain data without corruption, and approximate memory banks, where memory cells are subject to read/write faults with controlled probability. Approximate memories are part of the wider research topic regarding approximate computing and error tolerant applications, in which errors in computation are allowed at different levels (data level, instruction level, algorithmic level). In general these errors are the result of circuital or architectural techniques (i.e. voltage scaling, refresh rate reduction) which trade off energy savings for the occurrence of errors in data processing. The ability to support approximate memory in the OS is required by many proposed techniques which try to save energy by raising memory fault probability, but the requirements at OS level have never been described and an actual implementation has never been proposed. In this paper we provide an analysis of the requirements and a description of the implementation of approximate memory management. Our approach allows Linux kernel to be aware of exact (normal) and approximate physical memories, managing them as a whole for the common part (e.g. optimization algorithms, page reuse) but distinguishing them in term of allocation requests and page pools management. The new kernel has been built and extensively tested on a hardware ×86 platform, showing the correctness of the implementation and of the fallback allocation policies
Lysine methyltransferases and their inhibitors
No full textSince 2000, the histone methyltransferases that catalyze the methylation of a number of histone and nonhistone substrates have been discovered. A growing body of literature is indicating that lysine methyltransferases (KMTs) play a crucial role for transcriptional regulation and are involved in cancer and. various other human diseases, thus being of high interest as potential therapeutic targets.
In this book chapter, we highlight the discovery, characterization, and application of selective KMT inhibitors, useful for dissecting their physiological functions as well as their disease implications. Over the past decade, there has been an impressive progress regarding the KMT inhibitor discovery, especially conjugating the research interest with the available and novel techniques including new assay methods, high-throughput screening structural biology, and medicinal chemistry approaches. Our goal is to point out herein key advances, challenges, possible future opportunities, and directions, regarding KMT modulation in a preclinical and clinical setting
EZH2 inhibitors: a patent review (2014-2016)
No full textThe histone methyltransferase EZH2 is the catalytic subunit of the PRC2 complex involved in H3K27 trimethylation. Aberrant PRC2 activity has been reported in several cancers and EZH2 overexpression has been associated with poor outcome in different tumors. EZH2 somatic mutations and deletions was found in lymphomas, myelodysplastic and myeloproliferative disorders and associated with higher H3K27me3 levels. Numerous chemical entities have been studied as EZH2 inhibitors in the recent years and some of them entered the cancer clinical arena. Areas covered: This review summarizes recent efforts in the drug development of EZH2 inhibitors reported in the patent literature covering the 2014-2016 period, and their potential use as therapeutics mainly in cancerous diseases. Expert opinion: Despite the number of compounds described, only a few of them entered the clinical arena. Moreover, most of the compounds developed share a common 2-pyridone ring pharmacophore. Recently, secondary mutants have been described to be resistant to the standard EZH2 inhibitors treatment. Based on these data a lot of effort is still required to find new chemical entities that inhibit EZH2 directly, or indirectly (via PRC2 disruption). Several issues are still to be settled, such as drug resistance and the importance of selectivity over EZH1 or somatic EZH2 mutants
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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