Polymeric Nanoparticle PET/MR Imaging Allows Macrophage Detection in Atherosclerotic Plaques

Author Manuscript 2013 March 02.Rationale: Myeloid cell content in atherosclerotic plaques associates with rupture and thrombosis. Thus, imaging of lesional monocytes and macrophages could serve as a biomarker of disease progression and therapeutic intervention. Objective: To noninvasively assess plaque inflammation with dextran nanoparticle (DNP)-facilitated hybrid positron emission tomography/magnetic resonance imaging (PET/MRI). Methods and Results: Using clinically approved building blocks, we systematically developed 13-nm polymeric nanoparticles consisting of cross-linked short chain dextrans, which were modified with desferoxamine for zirconium-89 radiolabeling ([superscript 89]Zr-DNP) and a near-infrared fluorochrome (VT680) for microscopic and cellular validation. Flow cytometry of cells isolated from excised aortas showed DNP uptake predominantly in monocytes and macrophages (76.7%) and lower signal originating from other leukocytes, such as neutrophils and lymphocytes (11.8% and 0.7%, P<0.05 versus monocytes and macrophages). DNP colocalized with the myeloid cell marker CD11b on immunohistochemistry. PET/MRI revealed high uptake of [superscript 89]Zr-DNP in the aortic root of apolipoprotein E knock out (ApoE[superscript −/−]) mice (standard uptake value, ApoE[superscript −/−] mice versus wild-type controls, 1.9±0.28 versus 1.3±0.03; P<0.05), corroborated by ex vivo scintillation counting and autoradiography. Therapeutic silencing of the monocyte-recruiting receptor C-C chemokine receptor type 2 with short-interfering RNA decreased [superscript 89]Zr-DNP plaque signal (P<0.05) and inflammatory gene expression (P<0.05). Conclusions: Hybrid PET/MRI with a 13-nm DNP enables noninvasive assessment of inflammation in experimental atherosclerotic plaques and reports on therapeutic efficacy of anti-inflammatory therapy.National Heart, Lung, and Blood InstituteNational Institutes of Health (U.S.). Dept. of Health and Human Services (HHSN268201000044C)National Institutes of Health (U.S.). Dept. of Health and Human Services (R01-HL096576)National Institutes of Health (U.S.). Dept. of Health and Human Services (R01-HL095629)National Institutes of Health (U.S.). Dept. of Health and Human Services (T32-HL094301

Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice

Background—Exaggerated and prolonged inflammation after myocardial infarction (MI) accelerates left ventricular remodeling. Inflammatory pathways may present a therapeutic target to prevent post-MI heart failure. However, the appropriate magnitude and timing of interventions are largely unknown, in part because noninvasive monitoring tools are lacking. Here, we used nanoparticle-facilitated silencing of CCR2, the chemokine receptor that governs inflammatory Ly-6Chigh monocyte subset traffic, to reduce infarct inflammation in apolipoprotein E–deficient (apoE−/−) mice after MI. We used dual-target positron emission tomography/magnetic resonance imaging of transglutaminase factor XIII (FXIII) and myeloperoxidase (MPO) activity to monitor how monocyte subset–targeted RNAi altered infarct inflammation and healing. Methods and Results—Flow cytometry, gene expression analysis, and histology revealed reduced monocyte numbers and enhanced resolution of inflammation in infarcted hearts of apoE−/− mice that were treated with nanoparticle-encapsulated siRNA. To follow extracellular matrix cross-linking noninvasively, we developed a fluorine-18–labeled positron emission tomography agent (18F-FXIII). Recruitment of MPO-rich inflammatory leukocytes was imaged with a molecular magnetic resonance imaging sensor of MPO activity (MPO-Gd). Positron emission tomography/magnetic resonance imaging detected anti-inflammatory effects of intravenous nanoparticle-facilitated siRNA therapy (75% decrease of MPO-Gd signal; P<0.05), whereas 18F-FXIII positron emission tomography reflected unimpeded matrix cross-linking in the infarct. Silencing of CCR2 during the first week after MI improved ejection fraction on day 21 after MI from 29% to 35% (P<0.05). Conclusion—CCR2-targeted RNAi reduced recruitment of Ly-6Chigh monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling.National Heart, Lung, and Blood InstituteUnited States. Dept. of Health and Human Services (contract No. HHSN268201000044C)National Institutes of Health (U.S.) (grant R01-HL096576)National Institutes of Health (U.S.) (grant R01-HL095629)National Institutes of Health (U.S.) (grant T32-HL094301)Deutsche Forschungsgemeinschaft (HE-6382/1-1

Design Strategies for ARX with Provable Bounds: SPARX and LAX

We present, for the first time, a general strategy for designing ARX symmetric-key primitives with provable resistance against single-trail differential and linear cryptanalysis. The latter has been a long standing open problem in the area of ARX design. The Wide-Trail design Strategy (WTS), that is at the basis of many S-box based ciphers, including the AES, is not suitable for ARX designs due to the lack of S-boxes in the latter. In this paper we address the mentioned limitation by proposing the Long-Trail design Strategy (LTS) -- a dual of the WTS that is applicable (but not limited) to ARX constructions. In contrast to the WTS, that prescribes the use of small and efficient S-boxes at the expense of heavy linear layers with strong mixing properties, the LTS advocates the use of large (ARX-based) S-Boxes together with sparse linear layers. With the help of the so-called long-trail argument, a designer can bound the maximum differential and linear probabilities for any number of rounds of a cipher built according to the LTS. To illustrate the effectiveness of the new strategy, we propose Sparx -- a family of ARX-based block ciphers designed according to the LTS. Sparx has 32-bit ARX-based S-boxes and has provable bounds against differential and linear cryptanalysis. In addition, Sparx is very efficient on a number of embedded platforms. Its optimized software implementation ranks in the top-6 of the most software-efficient ciphers along with Simon, Speck, Chaskey, LEA and RECTANGLE. As a second contribution we propose another strategy for designing ARX ciphers with provable properties, that is completely independent of the LTS. It is motivated by a challenge proposed earlier by Wallen and uses the differential properties of modular addition to minimize the maximum differential probability across multiple rounds of a cipher. A new primitive, called LAX is designed following those principles. LAX partly solves the Wallen challenge

Mind the Gap - A Closer Look at the Security of Block Ciphers against Differential Cryptanalysis

Resistance against differential cryptanalysis is an important design criteria for any modern block cipher and most designs rely on finding some upper bound on probability of single differential characteristics. However, already at EUROCRYPT'91, Lai et al. comprehended that differential cryptanalysis rather uses differentials instead of single characteristics. In this paper, we consider exactly the gap between these two approaches and investigate this gap in the context of recent lightweight cryptographic primitives. This shows that for many recent designs like Midori, Skinny or Sparx one has to be careful as bounds from counting the number of active S-boxes only give an inaccurate evaluation of the best differential distinguishers. For several designs we found new differential distinguishers and show how this gap evolves. We found an 8-round differential distinguisher for Skinny-64 with a probability of 2−56.932−56.93, while the best single characteristic only suggests a probability of 2−722−72. Our approach is integrated into publicly available tools and can easily be used when developing new cryptographic primitives. Moreover, as differential cryptanalysis is critically dependent on the distribution over the keys for the probability of differentials, we provide experiments for some of these new differentials found, in order to confirm that our estimates for the probability are correct. While for Skinny-64 the distribution over the keys follows a Poisson distribution, as one would expect, we noticed that Speck-64 follows a bimodal distribution, and the distribution of Midori-64 suggests a large class of weak keys

Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer.

Background Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection.Methods Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures. Transcriptomic data, available for 168 samples, was also performed.Results Overall, 8.1% of patients in the RMH cohort had some evidence of dMMR, which associated with decreased overall survival. Higher MSINGS scores associated with dMMR, and these APCs were enriched for higher T cell infiltration and PD-L1 protein expression. Exome MSINGS scores strongly correlated with targeted panel MSINGS scores (r = 0.73, P < 0.0001), and higher MSINGS scores associated with dMMR mutational signatures in APC exomes. dMMR mutational signatures also associated with MMR gene mutations and increased immune cell, immune checkpoint, and T cell-associated transcripts. APC with dMMR mutational signatures overexpressed a variety of immune transcripts, including CD200R1, BTLA, PD-L1, PD-L2, ADORA2A, PIK3CG, and TIGIT.Conclusion These data could impact immune target selection, combination therapeutic strategy selection, and selection of predictive biomarkers for immunotherapy in APC.Funding We acknowledge funding support from Movember, Prostate Cancer UK, The Prostate Cancer Foundation, SU2C, and Cancer Research UK

Automatic Search of Attacks on Round-Reduced AES and Applications

In this paper, we describe versatile and powerful algorithms for searching guess-and-determine and meet-in-the-middle attacks on byte-oriented symmetric primitives. To demonstrate the strength of these tool, we show that they allows to automatically discover new attacks on round-reduced AES with very low data complexity, and to find improved attacks on the AES-based MACs Alpha-MAC and Pelican-MAC, and also on the AES-based stream cipher LEX. Finally, the tools can be used in the context of fault attacks. These algorithms exploit the algebraically simple byte-oriented structure of the AES. When the attack found by the tool are practical, they have been implemented and validated

Proving the security of AES substitutionpermutation network

Abstract. In this paper we study the substitution-permutation network (SPN) on which AES is based. We introduce AES ∗ , a SPN identical to AES except that fixed S-boxes are replaced by random and independent permutations. We prove that this construction resists linear and differential cryptanalysis with 4 inner rounds only, despite the huge cumulative effect of multipath characteristics that is induced by the symmetries of AES. We show that the DP and LP terms both tend towards 1/(2 128 −1) very fast when the number of round increases. This proves a conjecture by Keliher, Meijer, and Tavares. We further show that AES ∗ is immune to any iterated attack of order 1 after 10 rounds only, which substantially improves a previous result by Moriai and Vaudenay