Study and development of innovative strategies for energy-efficient cross-layer design of digital VLSI systems based on Approximate Computing

The increasing demand on requirements for high performance and energy efficiency in modern digital systems has led to the research of new design approaches that are able to go beyond the established energy-performance tradeoff. Looking at scientific literature, the Approximate Computing paradigm has been particularly prolific. Many applications in the domain of signal processing, multimedia, computer vision, machine learning are known to be particularly resilient to errors occurring on their input data and during computation, producing outputs that, although degraded, are still largely acceptable from the point of view of quality. The Approximate Computing design paradigm leverages the characteristics of this group of applications to develop circuits, architectures, algorithms that, by relaxing design constraints, perform their computations in an approximate or inexact manner reducing energy consumption. This PhD research aims to explore the design of hardware/software architectures based on Approximate Computing techniques, filling the gap in literature regarding effective applicability and deriving a systematic methodology to characterize its benefits and tradeoffs. The main contributions of this work are: -the introduction of approximate memory management inside the Linux OS, allowing dynamic allocation and de-allocation of approximate memory at user level, as for normal exact memory; - the development of an emulation environment for platforms with approximate memory units, where faults are injected during the simulation based on models that reproduce the effects on memory cells of circuital and architectural techniques for approximate memories; -the implementation and analysis of the impact of approximate memory hardware on real applications: the H.264 video encoder, internally modified to allocate selected data buffers in approximate memory, and signal processing applications (digital filter) using approximate memory for input/output buffers and tap registers; -the development of a fully reconfigurable and combinatorial floating point unit, which can work with reduced precision formats

Application of Small Epigenetic Modulators in Pediatric Medulloblastoma

Medulloblastoma is one of the most frequent among pediatric brain tumors, and it has been classified in various subgroups. Some of them already benefit from quite good therapeutic options, whereas others urgently need novel therapeutic approaches. Epigenetic modulators have long been studied in various types of cancer. Within this review, we summarize the main preclinical studies regarding epigenetic targets (such as HDAC, SIRT, BET, EZH2, G9a, LSD1, and DNMT) inhibitors in medulloblastoma. Furthermore, we shed light on the increasing number of applications of drug combinations as well as hybrid compounds involving epigenetic mechanisms. Nevertheless, in the studies published so far, mainly un-specific or old modulators have been used, and the PKs (brain permeability) have not been well-evaluated. Thus, these findings should be considered as a starting point for further improvement and not as a final result

Role of vasopressin in the treatment of anaphylactic shock in a child undergoing surgery for congenital heart disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>The incidence of anaphylactic reactions during anesthesia is between 1:5000 and 1:25000 and it is one of the few causes of mortality directly related to general anesthesia. The most important requirements in the treatment of this clinical condition are early diagnosis and maintenance of vital organ perfusion. Epinephrine administration is generally considered as the first line treatment of anaphylactic reactions. However, recently, new pharmacological approaches have been described in the treatment of different forms of vasoplegic shock.</p> <p>Case presentation</p> <p>We describe the case of a child who was undergoing surgery for ventricular septal defect, with an anaphylactic reaction to heparin that was refractory to epinephrine infusion and was effectively treated by low dose vasopressin infusion.</p> <p>Conclusion</p> <p>In case of anaphylactic shock, continuous infusion of low-dose vasopressin might be considered after inadequate response to epinephrine, fluid resuscitation and corticosteroid administration.</p

Identification of a novel quinoline-based DNA demethylating compound highly potent in cancer cells

Background DNA methyltransferases (DNMTs) are epigenetic enzymes involved in embryonic development, cell differentiation, epithelial to mesenchymal transition, and control of gene expression, whose overexpression or enhanced catalytic activity has been widely reported in cancer initiation and progression. To date, two DNMT inhibitors (DNMTi), 5-azacytidine (5-AZA) and 5-aza-2′-deoxycytidine (DAC), are approved for the treatment of myelodysplastic syndromes and acute myeloid leukemia. Nevertheless, they are chemically instable and quite toxic for healthy cells; thus, the discovery of novel DNMTi is urgent. Results Here, we report the identification of a new quinoline-based molecule, MC3353, as a non-nucleoside inhibitor and downregulator of DNMT. This compound was able, in promoter demethylating assays, to induce enhanced green fluorescence protein (EGFP) gene expression in HCT116 cells and transcription in a cytomegalovirus (CMV) promoter-driven luciferase reporter system in KG-1 cells. Moreover, MC3353 displayed a strong antiproliferative activity when tested on HCT116 colon cancer cells after 48 h of treatment at 0.5 μM. At higher doses, this compound provided a cytotoxic effect in double DNMT knockout HCT116 cells. MC3353 was also screened on a different panel of cancer cells (KG-1 and U-937 acute myeloid leukemia, RAJI Burkitts lymphoma, PC-3 prostate cancer, and MDA-MB-231 breast cancer), where it arrested cell proliferation and reduced viability after 48 h of treatment with IC50 values ranging from 0.3 to 0.9 μM. Compared to healthy cell models, MC3353 induced apoptosis (e.g., U-937 and KG-1 cells) or necrosis (e.g., RAJI cells) at lower concentrations. Importantly, together with the main DNMT3A enzyme inhibition, MC3353 was also able to downregulate the DNMT3A protein level in selected HCT116 and PC-3 cell lines. Additionally, this compound provided impairment of the epithelial-to-mesenchymal transition (EMT) by inducing E-cadherin while reducing matrix metalloproteinase (MMP2) mRNA and protein levels in PC-3 and HCT116 cells. Last, tested on a panel of primary osteosarcoma cell lines, MC3353 markedly inhibited cell growth with low single-digit micromolar IC50 ranging from 1.1 to 2.4 μM. Interestingly, in Saos-2 osteosarcoma cells, MC3353 induced both expression of genes and mineralized the matrix as evidence of osteosarcoma to osteoblast differentiation. Conclusions The present work describes MC3353 as a novel DNMTi displaying a stronger in cell demethylating ability than both 5-AZA and DAC, providing re-activation of the silenced ubiquitin C-terminal hydrolase L1 (UCHL1) gene. MC3353 displayed dose- and time-dependent antiproliferative activity in several cancer cell types, inducing cell death and affecting EMT through E-cadherin and MMP2 modulation. In addition, this compound proved efficacy even in primary osteosarcoma cell models, through the modulation of genes involved in osteoblast differentiation.This work was supported by COST Action CM1406 (PBA, LA, AM, SV); by Ricerca Finalizzata 2013 PE-2013-02355271 (AM); by PRIN 2016 (prot. 20152TE5PK) (AM, LA); by AIRC grants n. 19162 (AM), 17217 (LA), and 18843 (MT); by NIH funds n. R01GM114306 (AM) and BLUEPRINT n. 282510 (AM, LA); by Programma VALERE: Vanvitelli per la Ricerca (LA) and the Italian-Flag Project-EPIGEN (LA); and by Pasteur Institute-Cenci Bolognetti Foundation (MT). MS was supported by a Waxweiler grant for cancer prevention research from the Action Lions Vaincre le Cancer. CF is a recipient of a Télévie Luxembourg fellowship. The work at LBMCC was supported by the Recherche Cancer et Sang foundation, by the Recherches Scientifiques Luxembourg association, by the Een Häerz fir kriibskrank Kanner association, by the Action LIONS Vaincre le Cancer association, and by Télévie Luxembourg. MD was supported by the Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Korea; the Tumor Microenvironment GCRC (2011-0030001) from the National Research Foundation funded by the Ministry of Science and ICT of Korea; the Creative-Pioneering Researchers Program through Seoul National University (SNU) [Funding number: 370C-20160062]; and Brain Korea (BK) 21 Plus program, Korea

From epigenetics to lipid metabolism: different approaches to fight cancer

During 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

In 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)

EZH2 inhibitors: a patent review (2014-2016)

The 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

An emulator for approximate memory platforms based on QEmu

In 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