Intestinal stem cell injury and protection during cancer therapy
Radiation and chemotherapy remain the most effective and widely used cancer treatments. Despite improvements in the delivery, dosing or combination of treatments, significant toxicities to normal tissues remain. Approximately 70% of all cancer patients receive radiation therapy during their care, which plays a critical role in 25% of all cancer cures (1,2). There are currently more than 10 million cancer survivors in the United States, necessitating measures to reduce treatment-related side effects. A better understanding of the molecular and cellular basis of these treatments, the related side effects, and new interventions can help ameliorate or prevent short-term and long-term toxicities of cancer therapies (1-3).
Most patients undergoing radiation to the abdomen, pelvis, or rectum will develop acute enteritis, which is dose limiting, while 5% to 15% of them will develop chronic problems (3,4). Radiation enteropathy is classified as early (acute) or delayed (chronic) (3). Early radiation enteropathy occurs during or shortly after radiotherapy, characterized by the death of rapidly proliferating crypt cells, resulting in epithelial barrier breakdown and inflammation (radiation mucositis). Delayed radiation enteropathy occurs months or later after radiotherapy, characterized by intestinal dysfunction associated with vascular sclerosis and progressive intestinal wall fibrosis, a process involving a complex interplay of various cell types, factors, and extracellular matrix (3). Loss of intestinal stem and progenitor cells plays a key role in acute radiation side effects in abdominal radiotherapy (2), which has attracted great interests in radioprotective drugs (1,2).
Intestinal stem cells (ISCs)
The single-layer columnar epithelium of the small intestine is one of the most rapidly renewing tissues in an adult mammal with a renewal cycle estimated to be 3-5 days in mice. The intense proliferation that fuels this self renewal process is confined to the crypts (5-7). Differentiated epithelial cells such as absorptive enterocytes, mucus-secreting goblet cells, enteroendocrine cells, and Paneth cells are generally well-defined by morphology and markers (8-10). Deep crypt secretory cells (11) may represent the colon counterparts of Paneth cells. However, the precise location and characteristics of ISCs remained elusive for a long time. Studies in the 1970s and 1980s defined two major populations of ISCs based on their locations: the stem cell zone model proposed by Cheng and Leblond defined the crypt base columnar cells (CBCs) sandwiched between Paneth cells (6,8), and the +4 label retaining cells (LRC) proposed by Potten and colleagues appeared radiosensitive (12).
Identification of ISC markers and generation of reporter mice have led to an explosion of ISC studies in the last five years (10). Most adult stem cell niches are coinhabited by cycling and quiescent stem cells. In the intestine, lineage tracing experiments revealed that Lgr5(+) (13) cells are frequently cycling stem cells, while Bmi1(+) (14), mTert(+) (15), Hopx(+) (16) and Lrig1(+) (17,18) cells appear more quiescent (10). Additional ISC-enriched populations are marked by CD133 (19,20), Musashi-1 (21), or dye-exclusion (side population, SP) (22) without definitive lineage tracing data. Since the expression of some reporters does not always recapitulate that of endogenous stem cell markers (Table 1), efforts are underway to use cell surface markers for ISC isolation (35,36).
Another breakthrough in the ISC field is the successful culture of isolated crypts and ISCs (37) in so called enteroids (38) or organoids assays. Tracing experiments indicated that the Lgr5(+) stem-cell hierarchy is maintained in enteroids containing four major differentiated epithelial lineages. Since then, similar approaches have been used to culture Lgr5+ cells, crypts, or marker enriched cells from mouse and human GI tract (10). This “in vitro” clonogenic assay is expected to greatly help the understanding of stem cell injury and regeneration regulated by cell autonomous mechanisms, and certainly can be adapted to include niche components as discussed later.
Intestinal response to radiation and chemotherapy in mice
Radiation and chemotherapy cause DNA damage and selectively target rapidly proliferating cells such as cancer cells and normal cells that undergo rapid self renewal, including those in the gastrointestinal (GI) tract. The response of the small intestine to ionizing radiation (IR) has been well characterized in mice, and damage to the clonogenic cells in the crypts through apoptosis plays an important role in IR-induced acute GI damage (34). Radiation at 8 Gy or lower doses causes obvious apoptosis in the crypts, and subsequent shortening of villi over a period of 5-7 days. This is followed by full recovery, suggesting little or no permanent injury to the stem cell compartment. After receiving greater than 14 Gy of total body irradiation (TBI), mice die between 7 and 12 days due to damage to the small intestine and complications known as GI syndrome, which cannot be rescued by bone marrow (BM) transplantation (34,39,40), or by any approved treatment. This higher dose causes complete sterilization of most crypts and severe loss of the epithelium, accompanied by a powerful regenerative response measured using a micro colony assay 3-4 days post IR (41,42). This so-called clonal regeneration process with characteristic regenerated crypts is widely used as the “in vivo” clonogenic assay. Therefore, apoptosis, cell proliferation, micro colony assays, and animal survival following 14 Gy (or higher) TBI or subtotal body irradiation have traditionally been used to assess ISC injury (34).
Radiation responses of several ISC populations have recently been examined in mice (Table 1). High doses of radiation (12 Gy or higher) cause loss of CBCs (23,25,26), and activation of quiescent stem cells (10,33) (Figure 1). Some early progenitors can revert back to stem cells only after IR, showing more efficient lineage tracing and formation of enteroids. These include some label retaining cells (LRC) (29), delta ligand expressing Dll1+ cells (31), and Sox9-GFP high cells (32), all expressing Lgr 5 in the +4 region (+3-+7), where transiently amplifying (TA) cells also reside. LRC/Paneth cells also appear to enter cell cycle after IR (30). The chemotherapeutic agent doxorubicin (Adriamycin) caused increased SP before crypt regeneration (22,33). With in-depth gene expression analysis (27) and single cell transcripts analysis (24), a picture is emerging that ISC populations and early progenitors are plastic, overlap in gene expression profiles, and can interconvert upon injury or genetic ablation, while fully recovered crypts resume the CBC/Paneth cell pattern at the crypt base (Figure 1) (10). The relative contribution of these populations to regeneration, their overlap, activation mechanisms, and the effects of radiation on marker expression remain to be determined.
Pathways controlling GI and ISC injury in response to genotoxic stress
IR-induced acute GI injury is characterized by a rapid loss of stem cells, breach in barrier function and lethality, in a time frame coinciding with the 5-day renewal cycle. Current understanding of DNA damage-induced intestinal injury came largely from genetically manipulated mice. Radiation-induced stem cell killing is controlled by p53-dependent early apoptosis and late mitotic death suppressed by p53. Regulators in DNA damage sensing, replication and repair, checkpoint functions and apoptosis significantly impact crypt radiosensitivity, consistent with generally cell autonomous mechanisms of DNA damage response as defined in humans, mice and other model organisms (43,44).
p53—a paradoxical role in IR-induced GI injury
p53 is one of the most important proteins protecting against carcinogenesis in mammals, and yet its activation by severe genotoxic stress leads to p53-dependent pathologies (45). Upon activation, p53 engages transcriptional programs to initiate apoptosis and cell cycle arrest, with opposing roles in cell survival (45-47). The BH3-only protein PUMA (48) and cyclin-dependent kinase (CDK) inhibitor p21 (49) are two major p53 effectors (Figure 2). p53 activation and responses are highly tissue-specific, likely reflecting selective activation of downstream p53 targets (45,46). Radiosensitive tissues tend to have high levels of p53 activity (50,51) and induction of apoptosis and apoptotic targets (52,53), while radioresistance tissues show selective induction of cell cycle regulators with little or no apoptosis (54,55). Loss of p53 protects the hematopoietic (HP) system and skin against IR and chemotherapy-induced injuries (56,57), and the small intestine from chemotherapy-induced apoptosis and mucositis (58,59) by blocking apoptosis. However, loss of p53 unexpectedly exacerbates GI damage and accelerated GI syndrome (39,60) despite blocked apoptosis (60). Moreover, the delayed mitotic cell death in the crypts occurring 24 hours or later after IR is exacerbated by p53 loss (61).
PUMA and p21—the battle of killing and mending
The answer to the paradoxical role of p53 came from genetically uncoupling of two arms of p53 responses using mice that deficient in PUMA, p21 or both (PUMA/p21) (62). The induction of PUMA and p21 by IR was mostly p53-dependent in the GI epithelium. In PUMA knockout (KO) mice, the early apoptosis was blocked, leading to increased ISC survival and regeneration, animal survival after high dose irradiation (25). A strong protection was observed in the CBCs besides the +4 region (25,28). In p21 KO mice, cell cycle arrest and DNA repair was lost, leading to shortened survival, accelerated crypt regeneration associated with massive nonapoptotic cell death, aberrant cell-cycle progression, persistent DNA damage, rampant replication stress, and chromosomal instability. Lack of p21 induction in p53 KO mice, or in PUMA/p21 double knockout (DKO) mice drastically elevated the delayed mitotic death, which was most pronounced during crypt regeneration despite blocked early apoptosis (Figure 2) (62). Loss of p21 also led to reduced cell viability after DNA damage (46), and abolished GI protection by “super p53” (63,64) and HP protection by CDK4/6 inhibition after IR (65). PUMA deficiency strongly protected against IR-induced hematopoietic stem cell apoptosis and lethality (66-71), which might also require p21. It would be interesting to see if blocking PUMA-dependent apoptosis potentiates p21 or p53-induced stem cell protection.
The Bcl-2 family is a group of evolutionarily conserved regulators of apoptosis induced by diverse stimuli (72,73), and executes p53-dependent apoptosis through the mitochondrial pathway following severe genotoxic stress (23,46,74). This family is further divided into three subfamilies based on their functions and structures: antiapoptotic Bcl-2 like proteins, Bax-like proapoptotic members, and the BH3-only proapoptotic members such as PUMA and Noxa. The BH3-only proteins are responsible for sensing and transmitting apoptotic signals to other Bcl-2 family members (74). Mice deficient in NOXA (75), also a p53 target, BAX or BAK (25,76), or BAX and BAK in the GI epithelium (63) were resistance to IR-induced crypt apoptosis, but BAX or BAK appear to mediate crypt apoptosis and survival only at GI-toxic doses, unlike their largely overlapping functions in development (77). BCL-2 KO (78) or BCL-w KO (79) mice showed increased apoptosis with 5-fluorouracil (5-FU) treatment or IR in the small intestinal crypts (80). In contrast, the Bcl-2 family plays little or no role in spontaneous crypt apoptosis (81).
DNA repair proteins
Deficiency in DNA repair proteins generally elevates intestinal radiosensitivity. ATM (ataxia telangiectasia mutated) KO mice showed accelerated GI-injury and lethality (82). Knockout of 53BP1 (83), or poly ADP-ribosepolymerase-1 (PARP-1) (84), led to decreased crypt survival after treatment with alkylating agents or IR. Loss of RAD50, MRE11, or DNAPK reduced crypt survival, while enhanced Rad50 response engaged p53-dependent protection (85). These data suggest that DNA repair protects against radiation-induced stem cell loss, without affecting early apoptosis or cell cycle arrest (83). Nonapoptotic killing of ISCs due to failed DNA repair likely involve replication stress, persistence DNA damage and chromosomal instability, as found in p21 KO mice (62).
Mismatch repair (MMR) proteins
Mutations in MMR proteins are found in the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (86). In addition to repair of mismatch DNA lesions, MMR proteins appear to interact with the p53 pathway to engage apoptosis depending on the type of DNA lesions (87). Deletion of MSH2 (88), MLH1, or PMS2 (89,90) led to resistance to apoptosis induced by IR or chemotherapy [5-FU, cisplatin, temozolomide, and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)]. In these studies, MMR deficiency enhanced carcinogenesis likely by elevating stem cell survival and mutation rates, where MNNG did not cause significant ISC loss or GI injury.
ISC survival measured by micro colony assay is not always correlated with apoptosis or animal survival in mice deficient in p21, p53 or MSH2 (62,91). Inability to assess ISC apoptosis and the “quality” of regenerated crypts might help explain why it was only recently discovered that some Lgr5+ and +4 cells, opposed to transiently amplifying cells (TA cells), are resistant to IR up to 8 Gy (Table 1) (26,28) (JY unpublished data), and the p53/p21 axis suppresses mitotic death and accelerated crypt regeneration independent of apoptosis (62). Therefore, parameters such as non-apoptotic cell death, the timing of crypt regeneration, DNA damage, and villus length should be considered to better measure ISC responses to IR.
Nuclear factor kappa B (NF-κB)
NF-κB regulates a wide variety of cellular functions, such as survival, proliferation, migration, and immune response, and its persistent activation leads to inflammation and cancer (92). TBI activated NF-κB/RelA heterodimers (93). NF-κB p50 KO mice showed elevated crypt apoptosis and sensitivity to IR-induced lethality and decreased crypt survival (93). Intestinal deletion of NF-κB/p65 activator IKKbeta led to increased epithelial apoptosis without treatment (94), suggesting transient NF-κB activation might improve ISC survival.
Prostaglandins (PGs) and Cox1 and Cox2
Prostaglandins are lipid second messengers that regulate intestinal epithelial apoptosis and proliferation, as well as immune responses. PGs are synthesized from arachidonic acid by either cyclooxygenase-1 (Cox-1) or cyclooxygenase-2 (Cox-2) (95). In particular, PGE2 shows strong radioprotective effects on the epithelium largely via the prostaglandin E2 receptor (EP2) (95). PGE2 suppressed IR-induced crypt apoptosis and enhanced crypt regeneration. PGE2 neutralizing antibody, COX1 KO, nonselective Cox inhibitors, but not COX2 KO, had opposite effects (96,97). These data suggest an important role of Cox1-mediated PGE2 production in the survival of irradiated ISCs.
The circadian clock is an evolutionarily conserved intrinsic timekeeping mechanism that controls daily variations in multiple biological processes (98). It has been known that intestinal proliferation, migration, and radiation response follow a circadian rhythm (12). Recent work showed that clock components regulate ISC (99) and hair follicle regeneration (100) in flies by coordinating cell cycle progression, stem cell division and gene expression (99). Interestingly, sensitivity to chemotherapy was also regulated by circadian rhythm (101), which can be suppressed by selenium in mice (102). These findings suggest novel ways for stem cell protection.
Regulation of radiation-induced ISC injury and regeneration by the “niche” and beyond
Stem cell function is controlled by extracellular cues from the niche in addition to intrinsic programs. The stem cell niche refers to cellular components and various signals found in their surrounding microenvironment, which collectively play a key role in stem cell self renewal and quiescence (103,104). Non-epithelial cells and soluble mediators can modulate the survival, differentiation or proliferation of ISCs and progenitors during injury. These include the BM (40), endothelial cells, mesenchymal cells, enteric neurons (104,105), immune cells (106), and growth factors or other ligands (107). As discussed below, understanding the effects of non-epithelial cells or factors are important for intestinal protection against cancer treatments.
Vascular endothelial cells
The concept that GI and crypt radiosensitivity is determined by vascular endothelial cells was primarily based on the antiapoptotic effects of bFGF, acid sphingomyelinase (also called ceramide synthase, ASMase) gene KO (108) or anti-ceramide antibody (109) in endothelial cells. Vascular endothelial dysfunction is involved in pathogenesis of early and delayed radiation enteropathy (110). However, several key findings argue against a significant role of endothelial cell loss in IR-induced acute apoptosis of ISCs occurring within hours. FGFR was expressed in ISCs not just endothelial cells (111). Growth factors and ASMase KO block IR-induced and p53-dependent apoptosis in ISCs (28) or lymphoid tissues (112). ISC protection occurred with minimal change in endothelial cells (25); and high dose IR caused “target” switching” to epithelial cells (82). All suggest a direct effect of these conditions on ISC apoptosis independent of those in endothelial cells. Using mice reconstituted with ASMase KO BM, crypt culture, or tissue specific KO should provide a more definitive answer.
Inflammation and immune cells
Inflammation plays an important role in radiation-induced injury, though the cellular and molecular targets are likely complex and remain poorly understood (106). GI epithelium interacts with a plethora of commensal and foreign antigens, making the gut mucosa a strong responsive organ in radiation-induced inflammation (106). The relatively poor therapeutic efficiency of “classic” anti-inflammatory strategies compared with the pathway agents discussed would suggest that ISC and epithelial injury is likely the trigger of lethal inflammatory responses. Production of inflammatory cytokines and immune cell infiltration negatively impacts ISCs further in the delayed phase via the niche and systemic effects (113-115). Therefore, opportunities might exist for exploiting the immune system to repair and heal gut epithelium with sufficient protection of ISCs in the acute phase.
Intestinal protection and mechanisms
Radiation protectors are agents that reduce normal tissue damage when administered before or at the time of radiation for effectiveness. Mitigators do so when administered even after radiation exposure. The major classes discussed below include antioxidents, growth factors, TRL ligands, apoptosis and cell cycle targeted agents and cell-based therapies. Almost all these agents suppress radiation-induced apoptosis and are more effective given before radiation, reinforcing the importance of ISC loss in the acute radiation injury. Some also protect against chemotherapy-induced GI injury, while a few promote ISC regeneration and suppress inflammation. Most of these agents are pleiotropic and act on the intestinal epithelium and other cell types (i.e., HP, immune and endothelial cells), making defining precise cellular targets difficult. Many new agents are in development and have shown promises in preclinical testing (1). On the other hand, stem cell protection might increase cancer risk upon expansion of damaged ISCs (116,117), a possibility which should be carefully assessed.
Antioxidants and natural products
Reactive oxygen species (ROS) are generated by IR and can directly damage DNA and other macromolecules, or cause damage indirectly by depleting cellular antioxidants (2). Various antioxidants, including plant-derived phytochemicals, and superoxide dismutase (SOD) gene therapy protect normal tissue from radiation-induced mild tissue injury, but have limited activities for IR-induced severe GI damage (118). The use of some antioxidants during radiotherapy was associated with poorer tumor control in human trials (1). Interestingly, PHY906, a four-herb Chinese medicine formula, reduced chemo-induced GI injury in clinical trials and mice without affecting tumor responses (119). The effects were associated with enhanced stem cell regeneration and Wnt signaling (119). However, the selectivity of PHY906 and other agents in this class in normal cells is generally not understood. Amifostine is the only approved radiation protector in clinical use that can reduce toxicity in the lung and hematopoietic system after chemotherapy or radiation (1).
A wide variety of growth factors and cytokines protect mice against radiation-induced GI injury and apoptosis, and improve crypt survival when administered before or shortly after IR (107). These include fibroblast growth factor 1(FGF-1) (120), basic fibroblast growth factor (bFGF or FGF-2) and related peptides, insulin-like growth factor 1 (IGF-1) (28,108,121,122), IGF transgenic (123), keratinocyte growth factor (KGF), transforming growth factor beta 3 (TGFβ3), interleukin 11 (107), antagonist of transforming growth factor beta 2 receptor (TGFβR2) (124), glucagon-like peptide-2 (GLP-2) (125), Lgr5 ligand R-Spondin 1 (126), and stem cell factor (SCF) (127,128). However, epidermal growth factor (EGF) was ineffective (129). KGF (130) and R-Spondin 1 also protected against chemotherapy-induced GI-injury and apoptosis, which is p53-dependent (58,59). Recent mechanistic studies indicate that IGF-1 and bFGF suppress p53-mediated PUMA expression and apoptosis in ISCs through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/MDM2 axis (28), perhaps a common mechanism underlying growth factor-mediated ISC protection. Palifermin, a recombinant human KGF, is approved for clinical use to reduce severe oral mucositis in cancer patients after myeloablative therapy with BM transplantation.
Pattern recognition receptors (PRRs) are proteins expressed on the surface of cells of the innate immune system that specifically recognize pathogen-associated molecular patterns (PAMPs) from microbial pathogens or cellular stress, and damage-associated molecular patterns (DAMPs) from cell components released during cell damage. They are also expressed on intestinal epithelial cells and are important in GI injury (131,132). Commensal bacteria activate Toll-like receptors (TLRs) and a variety of responses in different cells (131,132). Simulating TLR signaling by TLR4 ligand lipopolysaccharide (LPS) (133), TLR5 ligand Flagellin (134) and derivative CBLB502 (135), or TLR9 agonist (136), protects intestinal epithelium via NF-κB activation and apoptosis suppression (Figure 2). LPS or Flagellin are too proinflammatory to be useful radiation protectors. In contrast, CBLB502 suppressed “cytokine storm” and apoptosis in epithelial and endothelial cells, and effectively protected mice and rhesus monkeys against lethal TBI, given before or shortly after IR (135). Whether these agents engage p53-dependent responses in ISCs was unclear. Uncoupling NF-κB’s prosurvival and proinflammatory activities, much like the p53 pathway, might help find more effective radiation protectors.
Apoptosis and cell cycle targeted agents
A better understanding of p53 function in radiation-induced intestinal injury has an important implication. Unlike in the HP system, temporary suppression of p53 is predicted to be detrimental to the irradiated GI tract and ISCs. The differences between the HP and GI systems might reflect a significant difference in DNA repair in respective stem or progenitor compartments and is worth exploring (as discussed before). PUMA deficiency or p21 elevation did not significantly predispose mice to spontaneous carcinogenesis or aging (46,47). Small molecule PUMA inhibitors (137) and CDK inhibitors (69) are currently in development for radiation protection. Glycogen synthase kinase 3 (GSK3β) inhibitors might be another option by selectively blocking p53-dependent apoptosis (138). Growth factors might also suppress GSK3 via activation of PI3K/AKT (139).
Bone marrow-derived cells
Transplantation of large numbers of BM-derived cells protected against IR-induced GI injury, suppressed apoptosis and improved crypt and whole animal survival in mice. These include human mesenchymal stem cells (140,141), BM stromal cells (142), or whole marrow (143). BM-derived cells can give rise to several cell types outside of the hematopoietic system (144-146). However, even in the setting of GI injury, BM-derived cells were found to be incorporated into the human or mouse gastrointestinal tract at very low frequencies (147-149), excluding a direct role in tissue repair. Instead, paracrine signaling is likely to be important due to a systemic increase of growth factors such as bFGF, platelet-derived growth factor (PDGF), KGF and R-Spondin1 (142,143). The hematopoietic (CD45+) populations did not appear to play an important role in this process (142).
Successful cancer treatment by radiation and chemotherapy relies on selective killing of cancer cells with adequate protection of the normal tissue (133). Radiation and chemotherapy-induced GI injury is complex. In radiation-induced acute GI injury, both apoptotic and nonapoptotic cell death of ISCs play important roles and are largely regulated by cell-autonomous mechanisms. The epithelium and ISC injury in the delayed phase is less understood and involves additional cell types and the immune system. Understanding the differences between normal and tumor cells’ responses to genotoxic stress can lead to new rational approaches for selective protection of normal cells, such as suppression of p53-dependent apoptosis, enhanced DNA repair, activation of NF-κB, induced stem cell quiescence, and suppression of inflammation. Many challenges as well as opportunities lie ahead for GI protection against severe genotoxic stress. These will include the identification of additional regulators of ISC survival, better defining the role of non-epithelial cells and factors, and development of selective protectors. Crypt and ISC culture might prove to be a very useful model for many of these studies by enabling manipulation of pathways, validation of human relevance, and a high throughput platform for drug discovery. Lastly, short-term benefits of normal tissue and stem cell protection, and long-term risk of organ failure due to stem exhaustion or carcinogenesis due to damaged stem cells, need to be balanced.
The author would like to thank lab members for critical reading and discussion.
Funding: The work in author’s laboratory and this review is supported in part by NIH grants U01-DK085570, 1R01CA129829-01A1, American Cancer Society grant RGS-10-124-01-CCE (J Yu). The Yu laboratory is a member of the Intestinal Stem Cell Consortium, supported by NIDDK and NIAID (U01).
Provenance and Peer Review: This article was commissioned by the Guest Editors (Daohong Zhou and Chuan-Yuan Li) for the series “Stem Cells in Cancer” published in Translational Cancer Research. The article has undergone external peer review.
Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.3978/j.issn.2218-676X.2013.07.03). The series “Stem Cells in Cancer” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare.
Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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