Cancer incidence and age
The incidence of most malignant diseases increases with age. Approximately 55% of all newly diagnosed cancer cases and 70% of cancer-related deaths occur in patients aged 65 years or older (Yancik, 2005). The median age at death for the major tumours common to both males and females (lung, colorectal, lymphoma, leukaemia, pancreas, stomach) ranges from 71 to 77 years. As the world population ages, it is expected that the number of older patients with cancer will increase and therefore clinicians will be frequently confronted with older patients with cancer and treatment decisions in this population.
Definition of cell biology and carcinogenesis in an ageing perspective
Ageing principally contributes to carcinogenesis in two major ways: the passage of time per se leads to the accumulation of cells with multiple molecular alterations like mutations, eventually resulting in clinically manifest tumours. It is associated with important dysregulations in systemic homeostasis, especially in organs hosting tumours and in the immune and endocrine systems resulting in overall decreased tumorigenesis control. Hence, ageing is associated with numerous events at the molecular, cellular, and physiological levels that increase susceptibility to carcinogens, promote carcinogenesis, and decrease protective mechanisms (Anisimov, 2009).
Biological phenomena underlying carcinogenesis
Cellular senescence is a fundamental tumour suppression programme activated by different types of stresses (Rodier & Campisi, 2011; van Deursen, 2014). To curtail carcinogenesis, senescence acts to permanently prevent the continued proliferation of potential cancer cells, and can be seen as a safeguard barrier that limits the growth of pre-neoplastic cells early during cancer progression. Apart from their role in tumour suppression, senescent cells actively participate in normal tissue repair and in tissue remodelling during embryogenesis, functions most likely associated with a senescence-associated secretome that provides strong paracrine activities (Pérez-Mancera et al., 2014). This complex senescence-associated secretory phenotype (SASP) has a pro-inflammatory flavour and can display context-dependent biological behaviour, but discerning beneficial and detrimental effects on tissue microenvironments can be difficult. On the beneficial side, the SASP is critical for normal tissue repair and can reinforce the senescence proliferative arrest via autocrine or paracrine cytokine/chemokine signalling. The SASP can also help to manipulate the immune system into recognizing and destroying damaged cells. For example, the SASP can efficiently trigger or regulate the influx of several types of immune cells necessary for antitumoural immunity, mostly through pro-inflammatory cytokines or chemokines like IL-6 and IL-8 and chemoattractants like MCP-1 (Hoenicke & Zender, 2012).
Alternatively, the SASP also influences the microenvironment in ways that promote malignant phenotypes in neighbouring cancer cells including impaired differentiation or increased cancer cell growth, mesenchymal to epithelial transition and invasion, or finally, increased survival of neighbouring non-senescent cancer cells following cancer therapy (Campisi, 2001; Coppé et al., 2010). In summary, senescence is beneficial via its ability to prevent pre-neoplastic cell growth and to promote efficient tissue repair, but can be detrimental by diminishing proliferative cell pools and perturbing microenvironmental homeostasis. This duality accounts for the accumulation of senescent cells following tissue damage and explains how these resident senescent cells can lead to altered organ function including locally increased cancer cell growth.
Multiple signalling pathways regulate the senescence-associated growth arrest and SASP (Fig. 90.1). Deoxyribonucleic acid (DNA) damage, often the source of carcinogenic mutations, is considered as one of the most important senescence triggers (d’Adda di Fagagna, 2008). Cells that receive DNA lesions from exposure to endogenous or exogenous toxins activate a DNA damage response (DDR) that will regulate their subsequent fates ranging from transient growth arrest and DNA repair, to cell death, to extracellular alarm signals (Rodier et al., 2011). When DNA damage is beyond cellular repair capacity, but fails to initiate apoptosis, normal cells usually undergo DDR-regulated senescence via two key tumour suppressor signalling pathways, p53/p21WAF1 and p16INK4a/pRB. The DDR also converges on the transcription factor Nf-KB to regulate the SASP (Malaquin et al., 2015). Another important type of stress often associated with ageing that triggers cellular senescence is replicative exhaustion (i.e. normal cells can only undergo a finite number of divisions). Most often replicative senescence occurs via the shortening of the repeats at the ends of the chromosomes, called telomeres. Short telomeres have the potential to trigger genomic instability, but when telomeres reach a critically shortened length after numerous cell divisions, a DDR signalling cascade is initiated, resembling the response to direct DNA damage, resulting in a state of irreversible growth arrest. The excessive exposure of cells to acute or chronic oxidative stress also leads to stress-induced senescence resembling replicative exhaustion. Finally, another important senescence-inducing signal concerns the response to the activation of an oncogene or the loss of function of a tumour suppression gene, which both result in a state of cellular hyperproliferation, triggering the oncogene-induced senescence. Oncogene-induced senescence is a critical component of the beneficial antitumoural functions of senescence, as it prevents pre-neoplastic cell growth. Overall, the senescence response can be induced by diverse stimuli, but almost always involves the establishment and the maintenance of a permanent growth arrest concurrent with the apparition of a SASP.
Genomic instability/epigenetic modulation
Genomic instability is a hallmark of many human diseases, cancer, and progeroid syndromes representing the most common outcomes associated with the loss of genome integrity (Daniel & Tollefsbol, 2015; Belancio et al., 2015). The link between genomic instability, cancer, and ageing resides in the fact that the accumulation of mutations to a level that will be clinically manifest will take time. Genomic instability arises from either exogenous or endogenous sources. Numerous exogenous carcinogens, agents (IR, UV, cigarette smoke) are well-recognized. Among the endogenous sources of DNA damage are reactive oxygen species (ROS), replication errors, inflammation, and mitochondrial dysfunction (Vijg & Suh, 2013). How does genomic instability manifest itself? This can be small genetic changes such as single base pair substitutions or deletions as well as large genomic rearrangements such as deletions, inversions, or translocation often referred as chromosomal instability. All these mutations may contribute to carcinogenesis; however, the rate and spectrum of their accumulation show significant variations with age and with the tissues involved and can be greatly affected by various processes, including epigenetic modulation.
Epigenetics usually refers to heritable changes in genetic expression without changing the DNA sequence itself and it was recently recognized as important as genetics for health and disease (Brunet & Berger, 2014). The most important epigenetic mechanisms are DNA methylation, histone modification, and RNA interference (RNAi). Modification of histones involves changes within the basic structure of the chromatin unit known as nucleosome. Histone modification and the resulting configuration of the chromatin by methylation, ubuquitinylation, phosphorylation, biotinylation, or acetylation are associated with both activation and silencing of genes and can also lead to altered gene expression. Non-coding RNA such as micro-RNA (miRNA) can participate in the regulation of genes. miRNAs have the ability to supress gene expression by altering the stability of transcripts and targeting them for degradation; however. in some instances they have shown increased transcriptional activity (Tollefsbol, 2014). Thus, these processes can have important effects on both cancer incidence and progression. The hypermethylation of the promoters of certain cancer-related genes such as CDKN2A, RUNX3, and RARB can lead to their inactivation and subsequent genomic instability and cancer development. Inversely, hypomethylation can lead to the activation of certain oncogenes, contributing to the process of tumorigenesis. Aberrant methylation patterns are observed in almost all cancer including lung and breast, suggesting its importance as a molecular marker in cancer prevention, prognosis, and therapeutic approaches. Other epigenetic modifications such as aberrant histone modifications (e.g. HDAC1 and 2) are found in several cancers including prostate and gastric. These changes may also contribute to cancer progression and prognosis. Recent studies have also shown that aberrant expression of miRNA in cancer cells may contribute to both the onset of carcinogenesis, as well as the prognosis of various neoplasms (Ferdin et al., 2010). The catalytic subunit of the telomerase enzyme (hTERT) responsible for the maintenance of the telomeric ends is upregulated in almost 90% of cancers to avoid replicative cellular senescence, and is itself regulated by various epigenetic modifications such as acetylation of histones and promoter methylation. Carcinogenesis as well as its progression is often the result of epigenetic aberrations at various levels that lead to activation or deactivation of specific genes that are efficiently regulated in normal cells, but are further deregulated by the ageing process.
Ageing is associated with an oxidative stress, indicating a dysbalance between free radical production and defence (Harman, 2006). Normally cells are using oxygen to produce energy via the various metabolic pathways of the mitochondrion resulting in low levels of free radicals maintaining important cell functions such as signalling. During ageing, endogenous cell mitochondrial damages occur concomitantly to cell exogenous processes such as inflammation that lead to the increased production of free radicals and to decreased antioxidant defence. The damage caused by endogenous ROS has been proposed as a major contributor to both ageing and cancer. ROS may induce mutations in proto-oncogenes. A variety of cell defence systems are involved in protecting macromolecules against devastating action of ROS. These systems include antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase), some vitamins (α-tocopherol, ascorbic acid), uric acid, and the pineal indole hormone, melatonin. Accumulation with age of some spontaneous mutations can induce genome instability and, hence, increase the sensitivity to carcinogens and/or tumour promoters.
Oncogenes play an important role in carcinogenesis by directly promoting cell proliferation, but also by increasing cancer cells’ ability to modulate their microenvironment, and are counteracted by tumour suppressor genes regulating oncogene-induced senescence. In particular, myc and Ras are particularly well-described oncogenes originally identified during virus-induced carcinogenesis (Sewastianik et al., 2014; Schmukler et al., 2014).
Both carcinogenesis and ageing are associated with genomic alterations, which may act synergistically in causing cancer. In particular, three key age-related changes in DNA metabolism may favour cell transformation and cancer growth. These are genetic instability, DNA hypomethylation, and formation of DNA adducts. Genetic instability involves activation of genes that are normally suppressed, such as cellular proto-oncogenes, and/or inactivation of tumour suppressor genes (p53, Rb, and so on). DNA hypomethylation is characteristic of ageing, as well as of transformed cells. Hypomethylation, a potential mechanism of oncogene activation, may result in spontaneous deamination of cytosine and consequent base transition. Accumulation of inappropriate base pairs may cause cell transformation by activation of cellular proto-oncogenes. Age-related abnormalities of DNA metabolism may be, to some extent, tissue-and gene-specific. Within the same cell, different DNA segments express different degrees of age-related hypomethylation. The uneven distribution of hypomethylation may underlie selective overexpression of proto-oncogenes by senescent cells.
Ageing is associated with immunosenescence and a low-grade inflammation (called ‘inflamm-ageing’). Changes in the immune system via increased inflammation or decreased immunosurveillance may contribute to increased tumorigenesis during ageing (Fulop et al., 2013). Chronic inflammation was shown to play a significant role in cancer development (Aggarwal & Gehlot, 2009). The inflammation in ageing is chronic and low-grade, manifest by an increase in pro-inflammatory cytokines (mainly IL-1, IL-6, and TNF-α), chemokines (IL-8, RANTES, MCP-1), and C-reactive protein (CRP) even in healthy older persons. Although this remains to be clearly proven, it is suggested that the SASP emanating from accumulating resident senescent cells could be at least in part responsible for this effect.
The immune alterations include those resulting from the early thymic involution, changes in the number, distribution, and activity of T-and B-lymphocytes, reduced availability of naïve CD4+ and CD8+ T-cells, and reduced production of naïve B-cells (Pawelec et al., 2010). Recent cumulative evidence points towards age-associated changes in the cellular components of the innate immune system, including natural killer cells (NK), phagocytes and dendritic cells (Solana et al., 2012). An age-associated increase in peripheral blood CD4+CD25high regulatory T-cells (Treg), capable of decreasing cytotoxic activity of CD8+ T- and NK cells and reducing IL-2 production, has also been reported. Recently an increase in Myeloid derived suppressor cell number, shown as suppressor of the immune response to tumours, has been found in healthy elders (Verschoor et al., 2013). This adds another element to the possible contribution of immunosenescence to the carcinogenesis.
Nutrition and diet, via metabolic pathways, both in quantity and quality have been linked to ageing and cancer incidence and prognosis. Recently, it has been suggested that nutrition is the most influential of all external environmental factors due to its ability to affect the transcriptional activity and expression of numerous genes (Choi & Friso, 2010). Nutrition and diet carcinogenic effects have been shown to be mediated by various pathways such as epigenetic mechanisms, genomic modulation, hormonal changes, and metabolic changes. Cancer cells are known to metabolize glucose much more rapidly in comparison with normal cells. Warburg first described the paradoxical preference of cancer cells to metabolize glucose through glycolysis, even in the presence of ample amounts of oxygen where oxidative phosphorylation would be much more efficient to produce adenosine triphosphate (ATP). This apparent dependence on glucose of cancer cells has been successfully used in both cancer prognosis and monitoring. Glucose is intimately linked to the insulin/IGF-1 pathway influencing the cellular growth. Therefore, glucose overload can be either directly or indirectly via the IGF-1 linked to increased cancer incidence. These changes are decreasing the production of glucagon which inhibit autophagy and shift the cells from growth to cell replication, favouring cancer development. These effects are mediated by the mTOR pathway which depends on nutrient abundance and various cellular metabolic states.
These cell fate events are additional means to combat carcinogenesis (Ávalos et al., 2014). They can prevent the multiplication of transformed cells before cancer becomes clinically manifest. DNA damage that is not repaired will lead to apoptosis or cellular senescence, both fundamental mechanisms to prevent carcinogenesis. Alternatively, the role of autophagy relates to inhibition of the mTOR pathway and is well-recognized in carcinogenesis.
Autophagy represents an important catabolic mechanism that cancer cells activate in response to cellular stress and/or increased metabolic demands imposed by rapid cell proliferation. In this way, autophagy should favour tumour cell survival. Interestingly, however, autophagy also acts as a tumour suppressor mechanism by preventing the accumulation of damaged organelles and proteins. Most of the proteins that participate in the regulation of autophagy are either tumour suppressor proteins or oncogenes. Perhaps not surprisingly, mechanisms involved in the regulation of autophagy largely overlap with signalling pathways implicated in the control of cancer. Thus, tumour suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, and AKT, inhibit autophagy (Choi et al., 2013), The notion that autophagy represents a mechanism that promotes tumour growth is based on the necessity of tumoural cells to adapt to ischaemia in an environment that is hypoxic, as well as growth factor and nutrient deprived. These observations suggest a role for autophagy in promoting survival of tumour cells under conditions of metabolic stress. Moreover, the higher energy requirements can be satisfied by increasing autophagy as a mechanism that permits obtaining both ATP and metabolic intermediates. Importantly, for tumour cells in which the oncogene Ras is activated, high levels of basal autophagy and dependence on this mechanism for survival are observed (Guo et al., 2011). For these reasons, autophagy is thought to promote tumour cell survival by increasing stress tolerance and providing a pathway that permits obtaining the nutrients necessary to meet the enhanced energetic requirements of these cells.
Many cancers have been shown to be nutrient sensitive. Quantity of diet has been characterized as a powerful external environmental mechanism in both the extension of lifespan and the development and prognosis of various cancers. In most of the epidemiological studies, an inverse relationship was found between consumption of vegetables, fruits, and risks of carcinogenesis in the whole digestive tract, lung, endometrium, and pancreas (Signorelli et al., 2015). In colorectal cancers it has been proposed that dietary factors contribute to more than 70% of cases (Pericleous et al., 2013). Natural substances provide suppression of the inflammatory processes that are involved in cell hyperproliferation and transformation. These compounds may also suppress the final steps of carcinogenesis such as angiogenesis and metastasis formation. Thus the diet composition may play a strong carcinogenic role by its ability to affect the transcriptional activity and expression of certain genes. The quality of diet plays also an important role as modulator of carcinogenesis via the modulation of the epigenome and the Nrf2 pathway.
There are age-related differences in sensitivity to carcinogen in some tissues (Anisimov, 2009). The effective dose of carcinogen requiring metabolic activation may vary significantly in old and young organisms, because the activity of the enzymes necessary for carcinogen activation in the liver and/or target tissue(s) may change with age. Critical factors that determine the susceptibility of a tissue to carcinogenesis include DNA synthesis and proliferative activity of that tissue at the time of carcinogen exposure, and the efficacy of damaged DNA repair. The homeostatic regulation of cell numbers in normal tissues reflects a precise balance between cell proliferation and cell death. Recently it was shown that the lifetime risk of many different types of cancers is strongly correlated with the total number of divisions of the normal self-renewing cells maintaining that tissue’s homeostasis (Tomasetti & Vogelstein, 2015).
Carcinogenesis is a multistage process: neoplastic transformation implies the engagement of a cell through sequential stages, and different agents may affect the transition between continuous stages. Multistage carcinogenesis is accompanied by disturbances in tissue homeostasis and perturbations in nervous, hormonal, and metabolic factors which may affect antitumour resistance. The development of these changes depends on the susceptibility of various systems to a carcinogen and on the dose of the carcinogen. Changes in the microenvironment may condition key carcinogenic events and determine the duration of each carcinogenic stage, and sometimes they may even reverse the process of carcinogenesis. These microenvironmental changes influence the proliferation rate of transformed cells, the total duration of carcinogenesis and, consequently, the latent period of tumour development.
Light-at-night and circadian desynchronosis
Light-at-night (LAN) has become an increasing and essential part of modern lifestyle and leads to a number of health problems, including excess of body mass index, cardiovascular diseases, diabetes, and cancer (Knutsson, 2003). According to the circadian disruption hypothesis, LAN might disrupt the endogenous circadian rhythm, and specifically suppress nocturnal production of pineal hormone melatonin and its secretion in the blood (Anisimov et al., 2012).
The number of shift workers has increased in some branches of industry and ranged from 15 to 20% of the total workforce in developed countries. Main health problems among shift workers include sleep disorders, gastrointestinal diseases, increased incidence of cardiovascular diseases, metabolic disturbances, insulin resistance and glucose intolerance, and possibly, an increase in late-onset diabetes. The International Agency for Research on Cancer (IARC) Working Group concluded that ‘shift-work that involves circadian disruption is probably carcinogenic to humans’.
Potential ‘ageing biomarkers’ might provide additional prognostic/predictive information besides clinical evaluation (Kalia 2015). Because age biomarkers can integrate both life history and the effect of an individual genetic background, an accurate age biomarker could be used to evaluate cancer risks based on biological age rather than chronological age (Pallis et al., 2014). It must be emphasized, however, that valid and reliable biomarkers of ageing have not yet been identified and that none of the candidate markers have reached a sufficient level of evidence-based acceptance to allow their use in routine clinical practice. Nevertheless, the expression level of the senescence-associated gene p16INK4A is probably currently the best molecular age biomarker (Box 90.1).
Telomeres shorten at every cell division and in the absence of the enzyme telomerase they eventually trigger genome instability and cellular senescence. For this reason telomere length has gained considerable interest as a potential biomarker of ageing and cancer risk. Several retrospective studies have found a strong association between shorter telomere length and cancer risk, including bladder, breast, gastroesophageal, and lung cancers. Short telomere length has also been associated with negative prognosis in patients with such as colorectal cancer (Gertler et al., 2004). A longitudinal population-based study demonstrated a statistically significant correlation between short telomere length and higher cancer incidence and mortality (Willeit et al., 2010). On the other hand, many prospective studies failed to demonstrate any significant association between short telomere length in leukocytes and increased cancer risk. Additionally, other studies failed to demonstrate any association between telomere length and morbidity, or mortality in the older and especially in the oldest old (Bischoff et al., 2006). Although telomere biology is extremely interesting, the (prognostic/predictive) value of telomere length in an individual patient is not yet established, probably owing to high interindividual variability in telomere length.
Special cases of centenarians
The study of centenarians is meant to unravel at least some of the secrets behind exceptionally long life (Robert and Fulop, 2014), but much remains to be done. It is clear from the study of Sicilian or Okinawan centenarians that the secret of long life is a combination of genetics and environment. It is evident that centenarians are able to better combat existing cancers and that the cancer incidence is decreased after 90 years (Salvioli et al., 2009). Several cellular and molecular mechanisms explain these phenomena. Functional exonuclease 1 (EXO1) promoter variant is associated with prolonged life expectancy in centenarians (Nebel et al., 2009). A functional SNP in the promoter of the ‘ataxia telangiectasia mutated’ (ATM) gene which encodes a serine/threonine kinase that is recruited by DNA double strand breaks and activates key proteins of the DNA damage response, and was found to be associated with longevity. Furthermore, the oxidative stress is lower, the effects of low-grade inflammations are better managed, and the cell senescence is differentially handled. Together, exceptional longevity in centenarians related to decreased cancer incidence indicates that in fact, normal ageing is the best antithesis of cancer and that only some pathological aspects of ageing are linked to increased carcinogenesis.
Is it possible to reduce cancer incidence in old age?
One of the most important concepts recently introduced is the ‘epigenetic diet’ including soy (gensitein), grapes (resveratrol), cruciferous vegetables (sulphoraphane), and green tea (epigallocatchin-3-gallate), which have been shown to induce epigenetic mechanisms that protect against cancer (Hardy & Tollefsbol, 2011). They act through DNMT, HAT, and histone deacetylases (HDAC) inhibition and miRNA regulation.
Another diet, the Mediterranean diet, appears to modulate carcinogenesis via diminution of inflammation and oxidative stress resulting in less cardiovascular disease and cancer (Kakkoura et al., 2015; Wang et al., 2014). This diet is characterized by high consumption of vegetables, fruits, cereals, beans, nuts, and olive oil; moderate consumption of fish, white meat, eggs, dairy products, and alcohol; and low consumption of red meat, processed meats, and foods rich in sugars or fats, possessing anti-inflammatory, and antioxidant capacity.
The role of exercise to combat carcinogenesis is controversial. There is substantial evidence that exercise, either habitual exercise or more intense aerobic exercise, has strong cancer prevention effects especially for breast and colon cancers, ranging from 20 to 40% of prevention. The effects are more difficult to demonstrate in elderly subjects. However, a few studies have demonstrated a preventive effect for habitual exercises on ovarian cancer (Lee et al., 2013). Subsequent studies showing the inverse relationship between exercise and coronary heart studies have demonstrated that an inverse relationship also holds true in otherwise healthy older adults, as well as in many common diseases, including colon cancer and breast cancer.
Calorie restriction mimetics
Calorie restriction (CR) is the only known intervention in mammals that has been consistently shown to increase lifespan, reduce incidence, and retard the onset of age-related diseases, including cancer and diabetes. CR in rhesus monkeys has produced physiological responses strikingly similar to those observed in rodents and delayed the onset of age-related diseases, but effects on longevity were not consistent. The concept of CR mimetics is now being intensively explored (Ingram & Roth, 2015). The antidiabetic biguanides, phenformin, buformin, and metformin were observed to reduce hyperglycemia, improve glucose utilization, reduce, insulin, and IGF-1, reduce body weight and decrease metabolic immunodepression both in humans and rodents (Anisimov & Bartke, 2013). There is sufficient evidence for inhibitory effects of biguanides on spontaneous tumorigenesis, as well as carcinogenesis induced by various chemical agents, genetic modification, viral, and irradiation agents. Metformin also increased AMP-activated protein kinase activity and increased antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation.
Recent findings provide an evidence of inhibitory effects of metformin and rapamycin on the SASP interfering with IKK-β/NF-κB (Johnson et al., 2013)—an important step in hypothalamic programming of systemic ageing (Zhang et al., 2013) and in carcinogenesis (Anisimov, 2009). It remains to be shown whether antidiabetic, biguanides, and rapamycin can extend lifespan in humans. It was recently shown that patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls (Bannister et al., 2014).
The future of research in cancer
Due to recent advances in biology and genomics, it is becoming possible to personalize an individual’s cancer treatment based on the molecular characteristics of the tumour. In older people, however, host factors also become increasingly important for treatment decisions, especially relating to the risks of toxicity in compromised individuals, balanced with potential benefits. Personalized medicine in oncology should thus not only focus on treatment at the tumour level, but also personalization towards the individual with his/her specific general health status. Moreover, chemotherapy by itself is suspected to accelerate the process of ageing and, more specifically, immunosenescence. Therefore, it is of the utmost importance to consider the biological and clinical aspect of ageing in the context of cancer treatment.
Thus, given the complexity of the senescence process, using a combination of markers might be the best approach. Candidate biomarkers cover different aspects of ageing biology and include leukocyte telomere length, p16INK4a expression in T-lymphocytes, immunosenescence, and oxidative stress markers, circulating inflammatory mediators, genetic variability in ageing/longevity-related genes, and miRNA expression. These markers would allow adaptation of therapies based on the ageing biomarker profile leading to personalized treatment, better success, and quality of life.
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