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Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment

International Journal of Cardiology, January 2016, Pages 766 - 772

Abstract

Loss of muscle mass arises from an imbalance of protein synthesis and protein degradation. Potential triggers of muscle wasting and function are immobilization, loss of appetite, dystrophies and chronic diseases as well as aging. All these conditions lead to increased morbidity and mortality in patients, which makes it a timely matter to find new biomarkers to get a fast clinical diagnosis and to develop new therapies. This mini-review covers current developments in the field of biomarkers and drugs on cachexia and sarcopenia. Here, we reported about promising markers, e.g. tartrate-resistant acid phosphatase 5a (TRACP5a), and novel substances like Epigallocatechin-3-gallate (EGCg). In summary, the progress to combat muscle wasting is in full swing and perhaps diagnosis of muscle atrophy and of course patient treatments could be soon supported by improved and more helpful strategies.

Highlights

  • Updates on mechanisms of loss of muscle mass
  • Current developments in biomarker research for muscle mass
  • Update on new treatment developments to increase muscle mass

Keywords: Cachexia, Biomarker, Sarcopenia.

1. Introduction

Loss of muscle mass is commonly observed in chronic diseases like cancer, chronic heart failure (HF), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), cystic fibrosis, liver cirrhosis, Crohn's disease, rheumatoid arthritis, stroke and many neurodegenerative diseases as well as in HIV/AIDS, malaria, and tuberculosis [1], [2], and [3]. A serious complication of these chronic illnesses is cachexia. Cachexia is defined as weight loss greater than 5% of body weight in 12 months or less in the presence of chronic illness or as a body mass index (BMI) lower than 20 kg/m2. In addition, usually three of the following five criteria are required: decreased muscle strength, fatigue, anorexia, low fat-free mass index, increase of inflammation markers such as C-reactive protein or interleukin (IL)-6 as well as anemia or low serum albumin [4] and [5]. Loss of muscle mass and function, especially muscle strength and gait speed, associated with aging occur in sarcopenia [6] and [7]. Indeed, sarcopenia, cachexia and malnutrition are considered as the main causes of muscle wasting [8] and affect millions of elderly people and patients [9]. Moreover, muscle atrophy can develop independently from diseases and age through disuse of the muscles [10]. For a better classification and common language in medical science for “muscle wasting disease” there is a proposal to combine the concepts of muscle wasting, sarcopenia, frailty and cachexia by disease etiology and disease progression [8]. Patients with muscle atrophy show decreased muscle strength and therefore reduced quality of life, which is caused by a lower activity and increased exercise intolerance [11]. In sarcopenic patients, muscle wasting is frequently associated with loss of bone, which leads to a higher risk of hip and other fractures [12]. Hip fracture also results in loss of musculature due to disuse atrophy [13]. All these conditions lead to increased morbidity and mortality in patients [14], and therefore developments in biomarkers and treatment finding to improve patients' lives is necessary (for schematic representation of the process see Fig. 1). The reason for muscle atrophy is an imbalance of protein synthesis and protein degradation. Three major protein degradation pathways play a role in development of muscle wasting: (1) activation of the ubiquitin–proteasome-system (UPS), (2) apoptosis through caspase signaling and (3) autophagy [15].

gr1

Fig. 1 Muscle mass loss is caused by many reasons resulting in morbidity and mortality which makes it necessary to find appropriate biomarkers and treatment strategies to improve patients' quality of life.

2. Current developments on muscle mass loss

The UPS pathway, which is conserved from yeast to mammals, plays a major role in degradation of most short-lived proteins. Most targets are cell cycle regulatory proteins as well as misfolded proteins. The target proteins undergo an ATP-dependent ubiquitination marking the protein for degradation. Polyubiquinated proteins are subsequently degraded by the proteasome [16] while monoubiquitinated substrates are eliminated in lysosomes [17]. At the beginning of the reaction, ubiquitin binds to an ubiquitin activating enzyme (E1) and forms a thio-ester bond. This reaction allows ubiquitin to transfer to an ubiquitin conjugating enzyme (E2) followed by the formation of an isopeptide bond which finally leads to the binding of E2 to an ubiquitin ligase (E3). The ligase specifically recognizes the substrate protein and transfers ubiquitin to the target protein [18]. Subsequently, the target proteins are unfolded and degraded by an ATP-dependent process [19]. Two muscle-specific E3 ubiquitin ligases named muscle atrophy F-box (MAFbx, atrogin-1) and muscle RING finger-1 (MuRF-1) were first described in 2001 and are significantly up-regulated during muscle atrophy [20] and [21]. However, the loss of these E3-ligases only leads to partial protection against muscle wasting [20]. MAFbx was shown to target regulatory factors for protein synthesis like MyoD [22] and the eukaryotic initiation factor of protein synthesis elF3-f [23]. MuRF-1 binds to titin [24] and [25] and targets myofibrillar proteins like myosin heavy chain, myosin light chain and myosin-binding C [26]. Another muscle-specific ubiquitin ligase named tripartite motif 32 (TRIM32) was discovered in 2005 [27]. TRIM32 is thought to ubiquitinate the thick myofibrillar filament as well as actin and dysbindin [27]. A muscle-specific F-box protein (FBXO40) was found in 2007 [28], which induces the ubiquitination of insulin receptor substrate 1 (IRS-1) thereby providing a negative feedback on the IGF1R/IRS1/PI3K/Akt pathway by early signal termination [29]. Moreover in 2010, TNF receptor-associated factor (TRAF6) has been found to play a critical role in atrophy as an E3 ubiquitin ligase [30].

Cancer cachexia animal models show significant wasting of the myocardium [31], [32], and [33]. In one study it was shown that the heart muscle weight decreased by 20% on average [34]. In another cancer cachexia study, cardiac wasting was associated with left-ventricular (LV)-dysfunction [35]. Treatment with selected agents (bisoprolol, spirolactone, imidapril) used in HF resulted in placebo-treated group of AH-130 rats in a loss of 21 ± 2% LV mass while the LV mass was stabilized by bisoprolol (+ 2 ± 8%, p < 0.0001) and increased by spirolactone (+ 9 ± 3%, p < 0.0001) whereas imidapril had no effect [35]. Moreover, a decrease in the trypsin-like activity of the UPS was seen in bisoprolol and spirolactone-treated animals in contrast to imidapril-treated ones which enhanced proteasome activity [35]. However, under oxidative stress conditions an upregulated expression level of the ubiquitin ligases MAFbx and MuRF-1 in cachectic hearts leads to the induction of the UPS [34]. MAFbx and MuRF-1 are elevated as well at the mRNA level linked to the degradation of cardiac troponin I, α-actin-2 and MyoD which leads to impaired contractility [36]. Furthermore, another study showed a reduced heart rate and fractional shortening using echocardiography in the myocardium of cancer cachectic mice [37]. Elevated levels of reactive oxygen species in cachectic skeletal muscle has been linked to an activation of the UPS [38]. In general, cytokines including IL-1, IL-6, tumor necrosis factor (TNF)-α and interferon-γ have been shown to contribute to a net catabolism in skeletal muscle and to form a state of oxidative stress [39]. These cytokines lead to an activation of Nuclear Factor kappa-light-chain-enhancer of activated B-cells (NFκB) and forkhead transcription factors (FoxO) in muscle [40] resulting in increased proteolysis by inducing the expression of MAFbx and MuRF-1 [15]. The involvement of the NFκB pathway was originally observed in a model of disuse atrophy [41] where it binds directly to MuRF-1 [42]. Furthermore, increased oxidative stress activates the NFκB pathway [43]. Surprisingly, an inhibition of NFκB via the IkappaB kinase complex only partially rescues the phenotype of the cachectic gastrocnemius in a murine model of cancer cachexia [44]. The FoxO family members consist of three isoforms as FoxO1, FoxO3 and FoxO4. It was shown that FoxO1 and FoxO3a are significantly upregulated in cachectic muscles from Lewis Lung Carcinoma [45] and Colon 26 tumor-bearing mice [46]. FoxO1 is also upregulated in skeletal muscle in human cancer cachexia patients [47]. Thus, these findings strongly support the involvement of NFκB and FoxO in the process of muscle atrophy. However, mitochondrial dysfunction and loss of mitochondria in skeletal muscle contribute to disrupted muscle function [48]. Indeed, investigations with markers of mitochondrial function and activity like the mitochondrial enzymes pyruvate dehydrogenase (PDH) and the cytochrome c oxidase (COX) showed that the protein concentrations of PDH and COX in the skeletal muscle of colon cancer patients decreased and a lower activity of PDH was observed as well [49].

Despite a large number of studies, our understanding of the development of muscle wasting and the involved pathways remains very limited. For instance, in some diseases like rheumatoid arthritis (RA) muscle wasting is not well investigated yet [50], [51], and [52], but better understanding is imperative for designing further studies and to develop new therapies. A recent study was aimed at an evaluation of muscle atrophy in skeletal muscle in a mouse model of RA and to establish a relation between disease score and muscle wasting [53]. Findings implicated the existence of a progressive development of muscle wasting with an early onset, which was especially associated with increased serum levels of cytokines, e.g. IL-6 [53]. Another not well studied muscle wasting disease is stroke, although it is known that stroke rapidly leads to an increase in muscle loss [54]. Hence, it is difficult to treat muscle atrophy in stroke patients. However, a large prospective stroke study with the main objectives to study changes in body composition, metabolic and functional changes of muscle tissue in patients with acute ischemic stroke is underway [55]. This study unites the knowledge of neurologists, cardiologists and endocrinologists and their findings might improve rehabilitation after stroke. Generally, impaired feeding, reduced caloric intake, and loss of appetite lead to a negative nutritional and nitrogen balance [56] and [57] and immobilization causes physical inactivity and muscle atrophy after stroke [58] and [59]. It has been shown that elevated volumes of TNF-α is responsible for muscle loss and that plasma concentrations of the enzyme visfatin were significantly elevated in patients after ischemic stroke [60] and [61]. For that, investigations of changes of inflammation parameters and its relation to body composition, insulin sensitivity and patient survival will be made as well [55].

2.0.1. Current news on biomarker research

Exact quantification of skeletal muscle mass is challenging. To better determine skeletal muscle mass, many measurement methods were developed in the last two centuries (for a historical overview see [62]). Since the early 1970s computed tomography (CT), magnet resonance imaging (MRI), and dual-energy X-ray absorptiometry (DXA) came into application [62]. A problem of these methods is that they are all expensive and thus only available at larger institutions. Moreover, these methods are only able to detect tissue wasting, but they are incapable of showing the risk of developing muscle atrophy [63] and [64]. But there is described a practical screening tool in a validated model to improve screening for low skeletal muscle mass in older adults [65]. It has been suggested that the BMI is strongly associated with a low skeletal muscle mass index (SMI) which could be helpful for primary care settings and treating elderly populations at risk of sarcopenia [65]. However, it is imperative to find new robust biomarkers, which are cheap and easily available for diagnosis and therapy monitoring in clinics [64]. Potential candidates are summarized in Table 1 and are described in more detail below. Serum creatinine may be such a reliable, cheap and easily accessible biomarker of skeletal muscle mass in human subjects, for example in CKD patients [66]. The adoption of liquid chromatography–tandem mass spectrometry (LC–MS/MS) based on D3-creatine dilution method from an oral dose and detection of urinary creatinine enrichment by isotope ratio mass spectrometry (IRMS) [67] could be an accurate tool to measure total body creatine skeletal muscle mass change [68]. The drawback of this method is the high cost and limited availability of the necessary machinery. Furthermore, serological neoepitopes have been suggested as muscle wasting biomarkers to solve some of these problems mentioned before. Neoepitopes do not reflect a condition or state like creatinine reflecting muscle mass, but a process which allows the early detection of muscle loss in disease. In fact, neoepitope biomarkers are parent proteins that are produced through posttranslational modifications, i.e. glycosylation, phosphorylation, acetylation, nitrosylation, methylation and ubiquitination of an existing molecule and are formed by protease cleavage or addition of chemical groups in tissues of interest [69]. The most common parent proteins for muscle loss biomarkers are sarcomeric proteins (e.g. myosin, actin, troponin, tropomyosin) and components of the extracellular matrix (e.g. laminins) [69]. That makes neoepitopes interesting to be biomarkers of muscle pathology [69]. Other serological biomarker candidates for muscle wasting are type VI collagen turnover-related peptides [70]. In a study, blood was analyzed for levels and their correlation of following biomarkers: an MMP-generated degradation fragment of collagen 6 (C6M) and a type VI collagen N-terminal globular domain epitope (IC6) [70]. These fragments can only be considered biomarker candidates of muscle mass and change in young men but not in elderly men [70]. However, circulating biomarkers like the N-terminal propeptide of type III procollagen (P3NP) and C-terminal agrin fragment (CAF) respond to resistance exercise training in older adults [71]. Short-time resistance exercise training (6 weeks) improves leg extension muscle strength, measured on a knee lift, by 29% from 39.7 ± 16.5 to 51.1 ± 18.3 kg in the exercise group (p < 0.001) and muscle quality by 28% from 3.64 ± 0.85 to 4.67 ± 0.81 relative strength (leg extension strength in kg/lean quadriceps muscle mass in kg) in the exercise group (p < 0.001) in older adults and may result in changes P3NP and CAF [71]. Indeed, CAF appears to increase in response to short-time resistance exercise training in older adults in contrast to P3NP where the results were less clear [71]. P3NP showed a positive correlation to changes in lean body mass (r = 0.422, p = 0.045) and there was observed a positive correlation between change in circulating CAF and change in cross-sectional area of the vastus lateralis (r = 0.542, p = 0.008) [71]. However, P3NP is associated with subsequent changes in lean body mass and appendicular skeletal muscle mass and seems to be a useful early predictive biomarker of anabolic response to growth hormone and testosterone [72]. 3-Methylhistidine (3MH) has been proposed as a marker of myofibrillar proteolysis through posttranslational methylation of specific histidine residues in actin and myosin [73], [74], [75], and [76]. In a clinical scenario, 3MH has to be determined quantitatively in urine or plasma collections. A major disadvantage is that meat-intake for 3 days prior to sample collection of patients can disturb the analysis of 3MH. A study from 2013 used 3MH, which was labeled with an isotope by using a nonradioactive isotope-based strategy [77]. The labeled methyl-d3-3MH (d-3MH) was taken orally by healthy men and urine and plasma samples were collected next day over 5–6 h, and were analyzed for d-3MH enrichment by gas chromatography–mass spectrometry [77]. The results suggest that it is possible to obtain an index of myofibrillar protein breakdown in urinary or plasma samples and that it is not necessary to quantify urine and plasma collections or to abstain from meat for several days [77]. Growth differentiating factor-15 (GDF-15) plays an important role in muscle wasting and cachexia [78]. Results from studies suggest that GDF-15 induces weight and muscle loss, which makes GDF-15 a promising marker of cachexia and muscle atrophy [79]. Myostatin is a known negative regulator of muscle growth and mass, which is associated with muscle wasting [78] suggesting it as a putative marker for muscle atrophy. However, this could not be confirmed in humans [80]. Interestingly, follistatin (FST), an endogenous, strong inhibitor of myostatin-mediated muscle wasting, has been suggested as a potential biomarker in sarcopenia [81]. FST binds to myostatin in the serum, thus, making myostatin often undetectable [82] and moreover, FST-overexpressing transgenic mice have shown a significant increase in muscle mass [83]. Therefore, FST seems to be a positive regulator of muscle growth which makes it interesting to be a biomarker. Irisin, the extracellular cleaved product of fibronectin type III domain containing protein 5 (FNDC5), seems to be a potential sarcopenia biomarker, because of its involvement in muscle physiology [81]. Plasma levels and mRNA expression of irisin were found to be elevated in mice in response to exercise [84]. Moreover, a positive correlation between circulating irisin and FST levels has been described in healthy men and obese persons [85]. Other than inflammatory cytokines, like IL-1, IL-6 and TNF-α, which are associated with anorexia and weight loss [86] and [87], hormonal factors have been postulated to play a role in development of muscle loss, especially in cachexia [88] and [89]. Such factors include for instance leptin [90], ghrelin [91] and obestatin [92] which are all thought to play a major role in cancer cachexia. These emerging biomarkers were investigated in oncologic patients as diagnostic and/or predictive markers, as well as their impact on patient survival [93]. The study showed that ghrelin and leptin may be promising biomarkers for the identification of cachexia related to cancer and mark survival in cancer patients [93]. Ghrelin serum levels were significantly higher in cancer patients in comparison to healthy subjects (573.31 ± 130 versus 320.20 ± 66.48 ng/ml, p < 0.0001) and levels of leptin were significantly lower in cancer patients than in healthy controls (38.4 ± 21.2 versus 76.28 ± 17.48 ng/ml, p < 0.0001) [93]. Ghrelin correlated negatively with leptin (r = − 0.75; p < 0.0001) and inversely as well [93]. By Kaplan Meier analysis, the survival prediction was tested and it was shown that patients with the best profile were those with low levels of ghrelin associated with high levels of leptin and in contrast patients with high ghrelin levels and low levels of leptin had a minor survival probability (log-rank (χ2) 8.02; p = 0.004) [93]. Furthermore, in a recently published study, in which a large number of putative biomarker candidates were tested, with a cohort of upper gastrointestinal cancer patients, β-dystroglycan was identified as a potential biomarker for weight-loss and myosin heavy chain (MyHC) or dystrophin as survival biomarkers [94]. As mentioned before, inflammatory cytokines are used for prognosis of cancer cachexia. A new promising chronic inflammatory marker was found recently and is suggested to play a prognostic role in cancer cachexia: the tartrate-resistant acid phosphatase 5a (TRACP5a) [95]. Moreover, it is already known that serum TRACP5a is elevated in patients with rheumatoid arthritis [96] and that the protein level of TRACP5a is reflected in cardiovascular diseases and sarcoidosis [97] and [98].

Table 1 Emerging candidates for biomarkers for cachexia and sarcopenia.

Emerging biomarkers for cachexia and sarcopenia
Creatinine [66]
Neoepitope [69]
MMP-generated degradation fragment of collagen 6 (C6M) [70]
Type VI collagen N-terminal globular domain epitope (IC6) [70]
N-terminal propeptide of type III procollagen (P3NP) [71]
C-terminal agrin fragment (CAF) [71]
Methyl-d3-methylhistidine (d-3MH) [77]
Growth differentiating factor-15 (GDF-15) [79]
Follistatin (FST) [81]
Irisin [81]
Ghrelin [93]
Leptin [93]
β-Dystroglycan [94]
Dystrophin [94]
Tartrate-resistant acid phosphatase 5a (TRACP5a) [95], [96], [97], and [98]

3. Current news on treatment

In 2013 & 2014, many new biomarkers, as described before, were investigated in different diseases and models. But although many researchers and pharmaceutical companies tried to find therapies for muscle atrophy, including cachexia and sarcopenia, no solution has been established until now [79], [99], and [100]. Interestingly, Morley et al. discussed if we are closer to having drugs for treating muscle wasting disease and therefore drugs were highlighted, which showed current advances in therapy for sarcopenia and cachexia (e.g. ghrelin agonists, selective androgen receptor molecules, megestrol acetate, activin receptor antagonists, espindolol, and fast skeletal muscle troponin inhibitors) [101]. Indeed, Morley et al. postulated that there is a remarkable increase in the knowledge of muscle wasting diseases due to new studies. However, a general strategy to avoid muscle mass loss and function is exercise [102] and [103]. Evidence of positive effects on frailty and sarcopenia through exercising are emerging [102], [104], [105], [106], [107], and [108]. Recently, an exercise investigation which focused on muscle quality in men and women aged 50 years and older suggested that long-term exercise, especially resistance exercise, is beneficial for muscle quality [109]. Interestingly, people over 60 years, who perform aerobic exercise once a week, also show positive association to muscle quality [109]. In rat skeletal muscle, an example for a successful result of exercising was postulated for glycogen synthase kinase-3β (GSK-3), which has a big therapeutical potential when it is inhibited [110]. An inhibition of the constitutively active kinase GSK-3β is considered to be beneficial, as it is involved in the regulatory inactivation of many anabolic pathways often leading to muscle wasting [111], [112], [113], [114], [115], and [116]. In detail, it has been demonstrated that physical exercise significantly decreases GSK-3β activity in rat skeletal muscle within 10 min of exercise and remained depressed with 30 and 60 min of exercise [110]. In the following part current treatment substance discoveries will be listed (see for detailed therapies [117] and [118]).

Ghrelin, which was delineated as a good biomarker before [93], and its analogs BIM-28125 and BIM-28131 seem to have a beneficial effect after administration in a rat heart failure study [119]. In that animal model it was shown that the expression of myostatin and the TNF-α concentration is significantly reduced in the gastrocnemius after treatment [119]. Moreover in a preclinical study, treatment with a ghrelin receptor agonist, named anamorelin, showed a significant and dose-dependent increased food intake as well as body weight compared with the vehicle control in healthy rats [120]. Thereby, with a treatment of anamorelin, a significant increase of growth hormone and insulin-like growth factor-1 plasma levels was observed in healthy female pigs in comparison to the placebos [120], which makes anamorelin a potential drug for treatment of cancer anorexia–cachexia syndrome. Espindolol, an anabolic catabolic transforming agent (ACTA), was used in a sarcopenia rat study [121]. Espindolol itself is a nonspecific β-1 and β-2 adrenergic receptor blocker with intrinsic sympathomimetic activity (ISA) on the β-2 adrenergic receptor which results in reduced catabolism and increased anabolism and espindolol is a highly potent antagonist of 5-HT1A receptors which has an effect on food-intake as well as reduced fatigue and thermogenesis [122]. A recent study, the ACT-ONE trial, which was a multicenter, randomized, double-blind and placebo-controlled study for dose-finding of espindolol in cachectic patients with non-small cell lung cancer and colorectal cancer in stages III and IV was started [122]. At the 7th Cachexia Conference, the first results of the ACT-ONE trial with 87 patients from 17 centers were presented [78]. Patients were treated with two doses of espindolol twice daily for 16 weeks. The results showed that the higher dose improves lean and fat mass and that the handgrip strength significantly increased at both doses [78]. Interestingly, in a rat sarcopenia model, espindolol treatment only had a small effect on overall body weight, but did significantly increase lean body mass, while at the same time reducing fat mass. This makes espindolol to an attractive candidate for treating sarcopenic patients, as these patients are often obese [121]. A highly potent β-2 adrenoceptor-selective agonist, formoterol, was used as a drug in a cancer cachexia rat model and it significantly reduced muscle wasting but had no influence on heart weight and function as often described in the literature [123]. Epigallocatechin-3-gallate (EGCg), which is a component of green tea, was published to be an effective inhibitor of increased protein degradation and depressed protein synthesis in an in vitro study by using murine C2C12 myotubes [124]. EGCg is not an approved drug but acts as a nutritional support and has been shown to attenuate skeletal muscle wasting in the Lewis lung carcinoma model of cancer cachexia [125].

4. Conclusions

Muscle loss arises from a dysbalance of catabolism and anabolism, i.e. protein degradation and protein synthesis. Despite a large number of studies, knowledge of disease related muscle wasting remains unclear. But investigations in the last two years like studies focusing on RA [53] and stroke [55] bring us one step ahead in understanding processes of muscle wasting due to those diseases. Cachectic and sarcopenic patients often suffer from quality of life including appetite loss and lower muscle strength, which makes finding appropriate biomarkers for diagnosis of muscle wasting associated diseases a timely mater. Although an “ideal” marker has not yet been identified, the development of some emerging candidates (Table 1) promises much potential. Neoepitopes [69] as biomarkers could be the solution for early diagnosis of a potential muscle mass loss allowing earlier detection and treatment to prevent morbidity and mortality in patients. In addition, finding new treatment strategies and drugs have to be developed to treat patient's symptoms. There are some very promising investigational drugs in studies related to cachexia and sarcopenia, but further research is necessary for a transition into the clinic. Maybe there is the need to combine existing treatment strategies with further novel approaches to treat muscle mass loss.

Disclosure

This paper is also published in parallel in the Journal of Cachexia, Sarcopenia and Muscle

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

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Footnotes

Innovative Clinical Trials, Department of Cardiology & Pneumology, University Medical Center Göttingen (UMG), Göttingen, Germany

Corresponding author at: Institute of Innovative Clinical Trials, Department of Cardiology & Pneumology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.


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