| 1. |
- Ashjaei, Seyed Mohammad Hossein, 1980-, et al.
(författare)
-
Modeling and Timing Analysis of Vehicle Functions Distributed over Switched Ethernet
- 2017
-
Ingår i: IECON 2017 - 43RD ANNUAL CONFERENCE OF THE IEEE INDUSTRIAL ELECTRONICS SOCIETY. - 9781538611272 ; , s. 8419-8424
-
Konferensbidrag (refereegranskat)abstract
- This paper proposes an approach to model switched Ethernet communication within a model- and component-based software development framework for vehicular distributed embedded systems. The paper also presents a method to extract the network timing model from the systems that use switched Ethernet networks. In order to provide a proof of concept, an existing industrial component model and its tool suite, namely RCM and Rubus-ICE respectively, are extended by implementing the modeling technique, the timing model extraction method and response-time analysis of the Ethernet AVB protocol. The extensions to RCM are backward compatible with the modeling and end-to-end timing analysis of traditional in-vehicle networks and legacy (previously developed) vehicular distributed embedded systems. Furthermore, the paper discusses the implementation and test strategy used in this work. Finally, the usability of the modeling approach and implemented timing analysis is demonstrated by modeling and time analyzing a vehicular application case study with the extended component model and tool suite.
|
|
| 2. |
- Gad, Helge, et al.
(författare)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
|
|
| 3. |
- Herold, Nikolas, et al.
(författare)
-
Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
-
Tidskriftsartikel (refereegranskat)abstract
- The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
|
|
| 4. |
- Llona-Minguez, Sabin, et al.
(författare)
-
Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1
- 2016
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:3, s. 1140-1148
-
Tidskriftsartikel (refereegranskat)abstract
- The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell sternness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.
|
|
| 5. |
- Llona-Minguez, Sabin, et al.
(författare)
-
Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part 2 : Pyridone- and pyrimidinone-derived systems
- 2017
-
Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X .- 1464-3405. ; 27:15, s. 3219-3225
-
Tidskriftsartikel (refereegranskat)abstract
- Two screening campaigns using commercial (Chembridge DiverSET) and proprietary (Chemical Biology Consortium Sweden, CBCS) compound libraries, revealed a number of pyridone- and pyrimidinone-derived systems as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). In this letter, we present their preliminary structure-activity-relationships (SAR) and ligand efficiency scores (LE and LLE).
|
|
| 6. |
- Llona-Minguez, Sabin, et al.
(författare)
-
Identification of Triazolothiadiazoles as Potent Inhibitors of the dCTP Pyrophosphatase 1
- 2017
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 60:5, s. 2148-2154
-
Tidskriftsartikel (refereegranskat)abstract
- The dCTP pyrophosphatase 1 (dCTPase) is involved in the regulation of the cellular dNTP pool and has been linked to cancer progression. Here we report on the discovery of a series of 3,6-disubstituted triazolothiadiazoles as potent dCTPase inhibitors. Compounds 16 and 18 display good correlation between enzymatic inhibition and target engagement, together with efficacy in a cellular synergy model, deeming them as a promising starting point for hit -to-lead development.
|
|
| 7. |
- Mubeen, Saad, et al.
(författare)
-
End-to-end Timing Analysis of Black-box Models in Legacy Vehicular Distributed Embedded Systems
- 2015
-
Ingår i: 21st IEEE International Conference on Embedded and Real-Time Computing Systems and Applications RTCSA'15. - 9781467378550 ; , s. 149-158
-
Konferensbidrag (refereegranskat)abstract
- A majority of existing techniques and tools, used in the vehicular industry, support the extraction of end-to-end timing models. Such models are used to perform timing analysis of distributed embedded systems at an abstraction level that is close to their implementation. This paper takes a first initiative to provide such a support at a higher level of abstraction. At such a level, the system can be modeled with inter-connected black-box models of nodes whose internal software architectures may not be available. However, most of the design decisions about network communication are available. This represents a typical scenario in the vehicular industry where most of the artifacts are reused from either legacy systems, other projects or previous releases of the vehicle. In this paper we present an approach for the extraction of end-to-end timing models at the highest level of abstraction used in the vehicular domain. Using these models, end-to-end path delay analysis of the systems can be performed at a higher abstraction level and at an early phase during the development. As a proof of concept we implement this technique in an industrial tool suite, Rubus-ICE, that is used for the development of these systems by several international companies. Using the extended tool, we conduct a vehicular-application case study.
|
|
| 8. |
- Mubeen, Saad, et al.
(författare)
-
Integrating Response-time Analysis for Heterogeneous Networks with Rubus Analysis Framework : Challenges and Preliminary Solutions
- 2015
-
Ingår i: 2015 IEEE 20th Conference on Emerging Technologies & Factory Automation (ETFA 2015). - 9781467379304
-
Konferensbidrag (refereegranskat)abstract
- In this paper we discuss the challenges that are faced when the state-of-the-art research results are transferred to a model-based tool chain for the industrial use. These challenges are often overlooked when the research results are implemented in an academic environment. In particular, we discuss various challenges regarding the implementation and integration of the response-time analysis for heterogeneous networks, comprising of CAN and Ethernet AVB, as a plug-in for the Rubus Analysis Framework. Rubus tool suite is used for the model- and component-based development of software for vehicular real-time systems by several international companies. We also discuss preliminary solutions to deal with the challenges.
|
|
| 9. |
- Mubeen, Saad, et al.
(författare)
-
Modeling of End-to-end Resource Reservations in Component-based Vehicular Embedded Systems
- 2016
-
Ingår i: Software Engineering and Advanced Applications (SEAA), 2016 42th Euromicro Conference on. - 9781509028191 ; , s. 283-292
-
Konferensbidrag (refereegranskat)abstract
- There is a plethora of models, techniques and toolsthat support model- and component-based software developmentof vehicular distributed embedded systems. However, a large ma-jority of them have a limited or no support to model and specifyend-to-end resource reservations on the software architecturesof these systems. Resource reservations allow flexibility duringthe development and execution of such complex systems withoutjeopardizing their predictable behavior. As a result, severalapplications in the system that share the same hardware platformcan be developed independently. In this paper we identify severalrequirements that any existing component model should fulfill inorder to support the modeling of end-to-end resource reservationson the software architectures of such systems. As a proof ofconcept, we extend the Rubus Component Model (RCM) byfulfilling these requirements. RCM is used for the development ofcontrol functionality in vehicular embedded systems by severalinternational companies. We also provide a technique to extractexecution models from the software architectures of these systemswith resource reservations. In order to show the usability of ourtechnique, we model a vehicular distributed embedded systemwith the extended component model and extract the executionmodel from the software architecture augmented with end-to-endresource reservations.
|
|
| 10. |
- Mubeen, Saad, et al.
(författare)
-
Modeling of Legacy Distributed Embedded Systems at Vehicle Abstraction Level
- 2016
-
Ingår i: Proceedings - 2016 19th International ACM SIGSOFT Symposium on Component-Based Software Engineering, CBSE 2016. - 9781509025695 ; , s. 7-12
-
Konferensbidrag (refereegranskat)abstract
- A large majority of existing software development approaches in the vehicle industrial domain have a limited or no modeling support to fully reuse legacy nodes at the highest abstraction, called the vehicle level. In this paper, we introduce a new technique for model-and component-based development of vehicular distributed embedded systems at the vehicle level. The proposed technique supports not only modeling of crude nodes or Electronic Control Units but also modeling of legacy nodes whose software architectures can be partially or completely reused. As a proof of concept, we implement the modeling technique in an industrial model, the Rubus Component Model. In order to show the usability of our approach, we model a vehicular application using the extended component model and its tool suite.
|
|
