Evolution of an Atherosclerotic Plaque: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Alexander B. Berdalin.

Atherosclerosis is a condition mediated by immune mechanisms, which is realized by the accumulation of lipoproteins in the wall of arterial vessels, leading to its focal thickening and the formation of atherosclerotic plaques in medium- and large-caliber arteries. Lipids, inflammatory infiltrates, smooth muscle cells, and connective tissue composes an atherosclerotic plaque, and a fibrous cap covers it. Damage to the latter leads to the fact that the internal contents of the plaque interact directly with the blood, which can cause thrombosis, and in the case of fragmentation of both the plaque and the blood clot on its surface—embolism in the distal vascular bed.

  • atherosclerosis
  • plaque
  • molecular imaging
  • preclinical
  • radiotracers
  • cardiovascular
  • pathophysiological

1. Fatty Streaks

Plaque evolution begins with the stage of “fatty streaks”, which are formed already in childhood and adolescence due to the accumulation of low- and very-low-density lipoproteins, their binding to proteoglycans in the intima, and the development of an inflammatory reaction leading to endotheliocyte activation. In the early stages, an increase in endotheliocyte permeability to low-density lipoproteins rich in cholesterol is observed, as well as an increase in the adhesive properties of the endothelial surface, which promotes monocyte migration from the vascular lumen to the subendothelial space [9][1]. The driver of increasing the adhesive properties of the endothelium is the adhesion molecules expressed on the cell surface, among which VCAM-1 and ICAM-1 (from the immunoglobulin superfamily) and P-selectins play a special role [10][2].

1.1. Labeled Lipoproteins

Visualization of fatty streaks in vivo is not important from the point of view of clinical practice: Timely lifestyle modification and normalization of lipid metabolism, according to Pitman et al. [11][3], may lead to their regression and reduce the risk of developing atherosclerosis in the future [12][4]. Nevertheless, radioactive labels containing low-density lipoproteins have been actively used to study lipid metabolism.
In particular, in 1988, the work of Vallabhajosula et al. was published, which compared radioactive labels for low-density lipoproteins and concluded that technetium-99m (99mTc) is preferred as such a label [13][5]. Vallabhajosula et al. have also demonstrated that in patients with hypercholesterolemia, 99mTc-labeled LDL is captured by actively developing atherosclerotic plaques and xanthomas that contain foam cells and macrophages [14][6]. Indium-111 (111In) and gallium-68 (68Ga) isotopes were also used as labels for LDL [15][7]. Rosen et al. found that the absorption of 111In-LDL in the proximal atherosclerotic aorta of rabbits with hypercholesterolemia was 2.5 times higher than in healthy animals [16][8]. Pirich and Sinzinger studied LDL metabolism in humans using radioactive iodine-123 and scintigraphy during therapy with isradipine and alprostadil [17][9]. In their study, in particular, it was demonstrated that the uptake of isotope-labeled LDL in atherosclerotic lesions provides valuable information for monitoring the natural course of the process, as well as evaluating the effectiveness of various types of interventions. Thus, the authors explained the anti-atherosclerotic activity of isradipine by its ability to stimulate the production of vascular prostaglandin IL-2, which leads to an increase in cAMP content and an increase in the action of cholesterol esterase. Moreover, Pietzsch et al. reported the development of fluoro-18 (18F)-labeled native and oxidized forms of LDL [18][10], which can be used in PET studies of fatty acid metabolism.
A few years ago, Pérez-Medina et al., using high-density lipoproteins labeled with zirconium-89 (89Zr), demonstrated that HDL accumulation in plaques is also increased [19][11]. In this study, it is stated that this isotope of zirconium is the preferred label for tracking lipid metabolism by PET due to its long half-life (78 h), which allows its accumulation in biological objects to be recorded for a long time. Studies were conducted on models of atherosclerosis in animals, including mice, rabbits, and pigs, and showed increased uptake of the studied radiopharmaceutical in the aorta compared with control animals without atherosclerosis. At the same time, the observed migration of labeled HDL particles into lipid plaques with signs of inflammation means that such particles are accumulated high-risk atheromas. Moreover, labeled HDL particles are recognized by the authors as promising radiopharmaceutical not only for visualization but also as a drug delivery system that transports drugs located in its core directly to those plaques that require therapy. In the editorial on the study of Pérez-Medina et al., it was indicated that although the particles, labeled with 89Zr, are unlikely to be available for studies in humans due to the long half-life of 89Zr (78 h) and, thus, large absorbed doses of radiation, the development of this technique may accelerate the stream of technology with the use of labeled HDL particles through the preclinical stage and to obtain important information about the effects of drugs on HDL metabolism [20][12].

1.2. Oxidized LDL

Oxidized LDL that is accumulated in the vessel wall is an attractive target for molecular imaging. Due to the fact that ex vivo monoclonal antibodies specific to oxidized forms are used for ex vivo staining of LDL, Tsimikas suggested that they also can be used in vivo to visualize the progression or regression of atherosclerotic lesions [21][13]. Plaque uptake of iodine-125 (125I)-labeled monoclonal antibodies has been shown to strongly correlate with the degree of atherosclerosis, measured as a percentage of the surface area or weight of the aorta, and thus provides an accurate quantitative assessment of the atherosclerotic load. In vivo scintigraphy with mouse antibodies to oxidized lipid forms has shown that visualization of atherosclerotic lesions is possible using this technique [21][13].
A potential target for molecular imaging of atherosclerosis may be oxidation-specific epitopes (OSE) since they exist at the intersection of oxidative stress, lipid metabolism, and inflammation. Lipid oxidation leads to the formation of highly reactive products that generate structural neoepitopes that are recognized by the body’s own immune system. Epitopes present on oxidized LDL stimulate their uptake by macrophages, contributing to their transformation into foam cells and the development of inflammation in the focus of atherosclerotic lesions. In addition, elevated concentrations of circulating epitopes of this type are associated with an increased risk of cardiovascular diseases [22][14]. Accordingly, OSE detection can be useful in objectifying the inflammatory process, which is especially important in atherosclerosis [23][15].
In 2002, the first human antibody capable of recognizing a unique epitope specific for oxidation was developed, which can also be labeled with appropriate labels for use in nuclear, magnetic resonance, or ultrasound imaging [21][13], though the development of such antibodies was initiated in 1990 [24][16]. The use of specific antibodies was demonstrated in laboratory animals, using the isotopes iodine-131 (131I) [25][17] and 125I [26][18] as labels. These methods were not used in the clinical setting.
To develop specific drugs, a library of antigen-binding fragments (Fabs) from human fetal cord blood was created in 2018. After several rounds of screening against the malondialdehyde-acetaldehyde (MAA) epitope, a specific fragment named LA25 was identified as an attractive candidate for creating RPs due to its specificity for the named epitope [27][19]. The study showed that LA25 specifically binds to MAA-carrying LDL and significantly inhibits their binding to macrophages. In tests performed on human coronary samples, LA25 was present in minimal amounts in areas with abnormal intimal thickening but accumulated in significant amounts in late forms of fibroatheroma and damaged plaques. PET labeling isotope, 89Zr, was used to label these antibodies. After an injection to ApoE-deficient mice, radioactivity in aortic plaques was more than three times higher for 89Zr-LA25 compared to the control Fab, 89Zr-LA24, as assessed by ex vivo autoradiography of the resected mouse aorta. In addition, the activity of 89Zr-LA25 was localized in areas rich in macrophages [26][18]. In the next stage, the authors used the indicator to visualize atherosclerotic lesions in larger animals. Using PET/MR, they observed a 32% increase in the uptake of the radioactive tracer in the aorta of rabbits with atherosclerosis compared to control animals. In addition, the accumulation of the radioactive indicator correlated with the area of the affected vessel wall, macrophage staining, and lipid content. It should be noted that the indicator virtually did not accumulate in the myocardium [27][19]. These in vivo observations support the assumption that OSE-rich plaques in humans can be visualized not only in the aorta but also in the coronary arteries due to the low accumulation of RP in the myocardium [23][15]. In a recent work by Zhang et al., oxidation-specific epitope imaging was described by means of other methods such as near-infrared and magnetic resonance imaging, which provides the possibility of plaque imaging with no radiation burden [28][20].
Directly oxidized LDL was also used as a radioactive label. In particular, Iuliano et al. found that 99mTc-labeled LDL is eliminated from the blood faster than native LDL, and its absorption in the liver is more intense. In addition, scintigrams of patients with atherosclerotic carotid artery disease showed significantly greater uptake of oxidized LDL forms in plaque compared to adequate controls [29][21]. Studies of oxidized LDL metabolism continue to date, including the use of 123I as a radioactive label [30][22], but the clinical significance of this radiopharmaceutical has not yet been determined.

1.3. Adhesion Molecules

Immunoglobulins and P-selectin expressed on the endothelial surface are promising potential targets at the considered stage of pathogenesis. For VCAM-1 visualization, Nahrendorf et al. developed an 18F-labeled compound 18F-4V, which is a linear tetrapeptide with a high tropicity to the expressed protein [31][23]. Later, Broisat et al. developed 99mTc-labeled nanobodies, cAbVCAM1-5. The latter are antibodies that contain only heavy chains, which are naturally present only in camels and are the smallest possible (10–15 kDa) functional immunoglobulin-like antigen-binding fragment [32,33][24][25]. In 2016, Bala et al. published a paper on the production of such nanobodies labeled with fluorine-18, which makes them suitable for use in PET/CT [34][26]. Regardless of the radioactive isotope used, the researchers managed to achieve high specificity of the developed tracers: The accumulation of RP in murine aortic plaques with signs of inflammation significantly exceeds that in normal tissues. However, VCAM-1 molecules are specific not only for atherosclerosis, but they are also expressed in any other inflammatory processes accompanied by endothelial activation, which leads to false-positive results. In addition, studies of these drugs were carried out mainly on laboratory animals and were not evaluated in clinical trials until the present moment, so their use outside the framework of clinical trials in humans is currently impossible.
VCAM-1 is present on the surface of cell membranes of the endothelial lining covering fibrous-cap atheromas and lipid-rich atheromas, as well as endotheliocytes of the new vasa vasorum, smooth muscle cells, and macrophages, according to Davies et al. [35][27]. According to O’Brien et al. [36][28], VCAM-1 expression on the smooth muscle cell membrane is significantly increased in atherosclerotic lesions of human coronary vessels, whereas its presence on the vascular endothelium is low in both the affected and control parts, which is associated with newly formed vessels of the vascular wall. Thus, the potential application of radioligands to VCAM-1 exists not only at the stage of lipid spots but also in later stages of atherosclerotic lesions. This explains the growing interest in the VCAM-1 imaging—in 2021, two new radiopharmaceuticals for this purpose were described by Pastorino et al. [37][29].
Two preclinical studies have focused on visualization based on labeled molecules that are tropic to P-selectin. In the work of Nakamura et al. radionuclide copper-64 (64Cu) was used, which was introduced as a label for monoclonal antibodies to P-selectin [38][30]. The distribution of such antibodies was studied using PET/CT, and histological examination of the aorta with autoradiography showed that antibodies selectively accumulated in atherosclerotic plaques. 64Cu has an important advantage of a long half-life, which is 12.7 h, which allows for studying slow biological processes and delayed imaging [39][31]. On the other hand, a longer half-life will result in a larger absorbed dose in the human body.
In another paper on visualization based on P-selectin binding, published by Li et al. [40][32], 68Ga-labeled fucoidan, a natural P-selectin ligand expressed on leukocytes and found in vivo as one of the products of brown algae processing, was chosen as the RP [41][33]. In his work, Li et al. convincingly showed that a significant accumulation of the radiopharmaceutical developed by them occurs in atherosclerotic lesions, in which high macrophage density and P-selectin expression are observed, while “inactive” atherosclerotic lesions accumulated RP to a much lesser extent. It is also important that the results of in vivo imaging were compared with tomograms obtained on an MRI with a magnetic field induction of 17.6 T, as well as the results of autoradiographic and histological analysis [40][32].
Recently, new probes targeted against P-selectin and VCAM-1 have been being at the stage of development. Like in some other targets, there is a shift to non-ionizing imaging of the inflamed endothelium and risk stratification of atherosclerosis with the use of dual-targeted microparticles of iron oxide and MRI [42][34].
The small size of fatty streaks causes difficulties in their visualization, which are associated with insufficient accumulated radioactivity in the vessel wall, low resolution of diagnostic equipment, and high radioactivity of the blood pool. Assessment of the accumulation of most of the noted RPs was carried out at the stage of formed atherosclerotic plaque, reflecting the activity of inflammatory reactions in its structure and, thus, the possible vulnerability of the atheroma.
It should be noted that all the above-mentioned RPs can be used to assess atherosclerotic changes at later stages of their development since the processes of lipid accumulation and inflammatory activation of the endothelium in plaque evolution continue constantly.

2. Macrophage Migration

The next step in the formation of atherosclerotic plaque is the accumulation of macrophages in the arterial walls. Upon entering the structure of the fatty streak, blood monocytes transform into macrophages and absorb lipoproteins, turning into xanthomous (or foam) cells. Extracellular proteoglycans secreted by smooth muscle cells also progressively bind lipids. The necrosis of macrophages and smooth muscle cells leads to the formation of necrotic residues and supports inflammation. The accumulation of extracellular lipids pooling together and resulting in cell necrosis also increases. Gradually, this leads to a distortion of the normal architecture of intima. Increasing pools form lipid-rich necrotic nuclei, which are usually located in the central part of the intima, and eventually occupy from 30% to 50% of the arterial wall volume [8,9][1][35].
At this stage, the main objects for visualization are macrophages expressing somatostatin type 2 receptors (SSTR2), mannose receptors (MR), folic acid receptors (FR), C-X-C chemokine receptors of type 4 (CXCR4), as well as their proliferation and increased glycolytic activity, and proteases secreted by them. In addition, molecular imaging of other white blood cells expressing an antigen associated with white blood cell function (LFA-1), specific markers of inflammation (translocation protein 18 kDa, TSPO, formerly known as the peripheral benzodiazepine receptor), markers of oxidized LDL accumulation (their LOX-1 receptor) are possible.

3. Plaque Formation

The fibrous tissue forms a capsule around the necrotic core of the plaque, and the part of this capsule located directly under the endothelium (at the border with the bloodstream) forms the plaque cap. The processes associated with the fibrous transformation of plaque are completed by the formation of a fibrous plaque (early fibroateroma)—the dominant substance of atherosclerosis. In addition to macrophage infiltration, atheroma also attracts other pro-inflammatory cells, in particular, T-lymphocytes [9,90][1][36].

3.1. Interleukin-2 Receptor

The interleukin-2 (IL-2) receptor overexpressed on activated T lymphocytes is a very attractive biomarker in assessing the vulnerability of plaques. Glaudemans et al. performed a visual analysis of scintigrams, and it revealed high uptake of a special RP affine to the IL-2 receptor, 99mTc-HYNIC-IL-2, in seven out of ten symptomatic atherosclerotic plaques, as well as SPECT/CT, allowed visualization in eight out of ten cases [91][37]. A correlation was also found between the number of CD25+ lymphocytes and the total number of CD25+ cells in the plaque, on the one hand, and the ratio between the target accumulation in the plaques and background uptake in the adjacent carotid artery, on the other. Micro-SPECT showed selective uptake of 99mTc-HYNIC-IL-2 in plaque components, excluding its lipid core [91][37].
Based on the presented data, it can be assumed that molecular imaging based on the binding of interleukin-2 receptors can be useful for verifying inflammatory processes in atherosclerotic plaques by the presence of activated T-lymphocytes in them. Annovazzi et al. came to a similar conclusion in their work with 99mTc-labeled interleukin-2 [92][38].

4. Thin-Capsule Fibroatheromas

In people over the age of 50, thin-capsule fibroateromas can form in the walls of blood vessels. The development of inflammation in fibrous plaques is mediated by macrophages, which secrete a significant amount of pro-inflammatory cytokines, reactive oxygen species, and blood clotting factor III, which promotes migration of monocytes, T-lymphocytes, and neutrophils into the plaque. In addition, migration is also facilitated by small vessels sprouting into the plaque (from vasa vasorum). Activation of apoptotic processes in plaques leads to a violation of the structure of the plaque capsule and causes the risk of its destruction. In other words, the plaque becomes vulnerable.

4.1. Neoangiogenesis

Neovascularization is considered one of the main factors of plaque vulnerability, and therefore specific imaging agents have been developed to detect newly formed vessels in the plaques. The target for such visualization is the integrin avβ3 expressed on macrophages, migrating smooth muscle cells, and endothelial cells in the vasa vasorum and intra-plaque microcirculation [93][39].
The tripeptide arginine-glycine-aspartic acid (RGD) has a high affinity for the integrin avβ3 and is often used as the main part of RPs targeting integrin. 18F-galacto-RGD has been shown to preferentially bind to damaged atherosclerotic plaques in the carotid arteries of patients within a few weeks after a stroke [94][40]. Saraste et al. performed experiments on mice, which showed that the use of 18F-galacto-RGD makes it possible to evaluate the effectiveness of treatment in atherosclerosis [95][41].
Among the disadvantages of 18F-galacto-RGD, the long time required for labeling is noted [93][39]. In this regard, the search and study of similar RPs, including 18F-Alphatide II and 68Ga-NOTA-PRGD2, have several advantages, including ease of preparation, fast labeling, and acceptable pharmacokinetics in vivo in comparison with most monomeric RGD peptides [96][42]. Another promising radiotracer is 18F-flotegatide, which also contains the RGD sequence [97][43].
Radiopharmaceuticals for the assessment of neoangiogenesis in plaques were also synthesized for SPECT. In particular, Vancraeynest et al. have shown that 99mTc-maracyclatide allows in vivo identification of plaques with signs of inflammation in mice and, thus, provides the possibility of non-invasive detection of high-risk plaques [98][44]. Other dimeric RPs (99mTc-IDA-D—[c(RGDfK)]2) also showed a high affinity for unstable atherosclerotic plaques, as it was reported by Sun Yoo et al. [99][45].
In addition to integrin, which is expressed not only on vascular cells, the vascular endothelial growth factor receptor, whose monoclonal antibodies were labeled with radioactive zirconium and tested in ex vivo experiments, can also be considered a target [100][46].

4.2. Hypoxia

Hypoxia refers to signs of plaque vulnerability due to insufficient perfusion in the large necrotic nucleus. In preclinical and clinical studies, RPs targeted to hypoxia sites were studied, among which 18F-FMISO is the most well-known and commercially available FMISO. Selective plaque uptake of 18F-fluoromizonadazole was demonstrated in a rabbit model of atherosclerosis [101][47]. In clinical studies, uptake of the highly specific hypoxia marker 18F-HX4 by carotid artery plaques has been observed in individuals who have suffered TIA due to plaque rupture [102][48].
A clinical trial by Joshi et al. including the results of the use of 18F-FMISO PET in 16 patients with recent TIA or stroke showed that the uptake of the radiopharmaceutical was slightly higher in symptomatic plaques on the affected side than in the plaques in contralateral arteries (TBR of 1.11 ± 0.07 vs. 1.05 ± 0.06; p < 0.05) and demonstrated a correlation with the activity of 18F-FDG, which confirms the role of hypoxia in the launch and maintenance of inflammation in the plaque [103][49].
Another possible method for hypoxia imaging is the 64Cu-ATSM PET/MRI, which was studied for atherosclerosis-associated hypoxia. Its main purpose is to detect hypoxia in tumors because this neutral lipophilic RP crosses membranes easily and undergoes reduction only in hypoxic cells and becomes trapped in these cells, while it is washed out from the normoxic cells [104][50]. This RP’s applicability to the PET/MR imaging of hypoxic atherosclerotic sites was demonstrated by Nie et al. [105][51]. It was demonstrated that in a rabbit model, this RP is a promising agent that colocalizes with immunohistochemical markers of the hypoxia. Recently, another preliminary clinical study was published by Nie et al. [106][52]. It demonstrates that the tracer is applicable for atherosclerotic plaque imaging, and RP’s uptake corresponds to hypoxic macrophages within the lipid-rich core of the plaque. 64Cu has a longer half-life time (12.7 h) that makes longer imaging intervals possible, but on the other hand, the absorbed dose is also higher, which leads us to the need for rigorous analysis of its benefits and risks, which is yet to be done.

4.3. Macrophage Death

99mTc-labeled annexin V has a high affinity for phosphatidylserine, which is located on the membrane of apoptotic cells. This RP is mainly used in oncology, but reports are available on its use in heart failure, after heart transplantation, and in atherosclerosis [107][53]. In a study by Kietselaer et al., in four individuals undergoing carotid endarterectomy, RP uptake correlated with high-risk plaque characteristics (macrophage infiltration and hemorrhage in the plaque matrix), which justifies the potential use of labeled annexin V in the identification of unstable plaques [108][54].
Similar RPs that are tropic to the necrotic component in the plaque structure were also developed for PET. In particular, 68Ga-labeled annexin V is detected by molecular imaging in plaques with necrotic lesions, as well as in matrix vesicles containing hydroxyapatite in atherosclerosis, which is explained by the fact that cell death can be one of the important stimuli for microcalcification [109][55]. 18F-ML-10 (2-(5-fluoropentyl)—2-methylmalonic acid) is a radiotracer for positron emission tomography (PET), which accumulates in cells with apoptosis-specific membrane changes. Hyafil et al. reported a strong correlation between the level of accumulation of 18F-ML-10 in different aortic segments recorded by autoradiography and the number of apoptotic cells on histological sections corresponding to the above-mentioned aortic segments in a rabbit model of atherosclerosis [110][56]. In addition, Pang et al. published data suggest that 18F-ML-10 may be useful for quantifying the vulnerability of atherosclerotic plaques rich in apoptotic cells [96,111][42][57].

4.4. Proteases

Vulnerable plaques are morphologically characterized by a thin fibrous cap covering the large lipid nucleus. Matrix metalloproteinases (MMPs) destroy the extracellular matrix that makes up the cap, which causes plaque destabilization and can be accompanied by the rupture of its cap. In addition, the above-mentioned LOX-1 also induces the expression and activation of MMP [112][58].
To visualize matrix metalloproteinases, RPs based on MMP inhibitors with radioactive labels were developed: 99mTc-RP805 (MPI), 111In-RP782, etc., which, as was shown in experiments, demonstrate higher accumulation in atherosclerotic altered vessels of mice with atherosclerosis compared to mice with intact vessels [113][59]. In model experiments by Fujimoto et al., it was shown that 99mTc-RP805 can also be used for dynamic monitoring of the state of a plaque during statin therapy [114][60]. Matrix metalloproteinase inhibitors were also labeled with other radionuclides, including positron-emitting ones, but these drugs were sparsely used [115][61].
In addition to specific MMP inhibitors, labeled antibodies to matrix metalloproteinases can also be used to visualize these molecules. In particular, a higher accumulation of 99mTc-labeled monoclonal antibodies to MT1-MMP was demonstrated in large atheromas (grade IV) compared to neointimal changes or other more stable atherosclerotic lesions [116][62]. The authors of this study indicate that further research is required to implement RP in practice.
Another strategy for molecular imaging of MMP is the use of labeled proteinase substrates, but studies of these experimental preparations have been only partially successful due to the non-specific uptake of RP [112,117][58][63].

5. Unstable Plaques

5.1. Calcification

Valuable data that is acquired during the molecular imaging procedures of the calcification process in clinical practice was discussed earlier [7][64].

5.2. Thrombosis

Blood clot formation caused by plaque rupture is the most important mechanism leading to acute MI and sudden cardiac death, as well as ischemic strokes. Thrombotic atheromas are an extremely important prognostic target for ranking the risk of vascular events and ensuring timely and effective treatment. Blood clotting factor III (tissue factor or tissue thromboplastin) initiates an exogenous blood clotting cascade that leads to the formation of a blood clot in vivo. In atherosclerotic lesions, it was identified in several cell types, including endothelial, smooth myocytes, monocytes, macrophages, and foam cells, but its expression increased at later stages of atheroma development [109][55].
99mTc-labeled monoclonal antibodies that have been proposed by Temma et al. can be used to visualize this type of molecule, and they showed six times more intense binding in the wall of the aorta affected by atherosclerosis in experimental animals compared to the control [118][65].
Since fibrin is localized in blood clots, rather than in circulating blood, the approach based on its visualization allows achieving high specificity in the detection of blood clots in particular, the EP-2104R molecule that consists of a short peptide that binds to fibrin and is conjugated with gadolinium as a contrast agent for MRI [119][66]. There is also information about a developed tracer with the radioactive label 64Cu-EP-2104R, which allows multimodal visualization of fibrin deposits in blood clots in rats [120][67].
In addition to the above data, there are isolated reports of the use of 111In-labeled platelets for the visualization of blood clots in atherosclerosis [121][68].

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