Abstract
This study investigated different bone biomarkers (cross-linked carboxy-terminal telopeptide of type 1 collagen (CTX-1), pyridinoline (PYD), osteocalcin (OC), interleukin-6 receptor (IL-6R), calcium (Ca), and magnesium (Mg)) in terms of their metabolism in 4 different leukemia subtypes (ALL, AML, CLL and CML). The design was case control study with 30 controls and 60 cases of leukemia patients. Authors have reported many results regarding decrease as well as increase of specific bone biomarker under investigation with each leukemia subtype when compared to control. In addition, Authors reported correlations between each biomarker level and leukemia subtypes.
Keywords: Bone remodelling, Imatinib, Osteoclasts, Osteoblasts, PYD, CTX-1
Introduction
Bones are continually adapted to different functional requirements. This adaptive process is known as remodeling, and it involves alternating the phenomena of resorption and bone formation to assure the management of bone homeostasis in the human body. The osteoblast/osteoclast balance is important in bone homeostasis and remodeling, as well as in bone fracture healing. Any imbalance in their activities leads to disorders like osteoporosis and Paget’s disease, which have serious consequences for the patient's life [1, 2].
Leukemia and its treatment have a negative influence on bone mineralization in children and adolescents. Chemotherapy (particularly glucocorticoids and methotrexate) is a key medicine used in ALL therapy that has a strong impact on demineralization and osteoclastogenesis [3]. Imatinib-treated CML patients have also been reported to have abnormalities in bone and mineral metabolism. These changes might be attributed to the drug's modulatory effects on osteoblasts and osteoclasts [4]. Furthermore, based on adult research, imatinib is well recognized to induce hypocalcemia and hypophosphatemia [5]. Biochemical indicators of bone turnover showed a biphasic response, with a rise in markers of bone formation followed by a reduction in markers of both formation and resorption [6]. There is mounting evidence that imatinib therapy may cause dysregulated bone remodeling [7].
Cytokines produced by leukemic cells promote osteoclast-mediated bone resorption, resulting in osteopenia and bone pain, and bone turnover marker levels are diminished prior to therapy. This suggests that the leukemic process is a key risk factor for reduced bone formation and that considerable bone damage occurs as a result of chemotherapeutic drugs [3]. Giannoni et al. revealed that CLL cells influence the development of the two primary bone components, osteoblasts and osteoclasts. Through the production of soluble substances, CLL cells limit osteoblast development while increasing osteoclastogenesis and bone resorption [8]. Another study by Chen et al. observed that AML-induced suppression of mature osteoblasts is represented by reduced peripheral blood osteocalcin levels at first diagnosis, which indicates long-term results in AML patients [9]. This suggests that the leukemic process itself is a major risk factor for reduced bone formation [10].
Hence, the aim of this study is to assess bone metabolism in leukemia subtypes by measuring biomarkers of bone cell activity. This study investigated levels of cross-linked carboxy-terminal telopeptide of type 1 collagen (CTX-1), pyridinoline (PYD), osteocalcin (OC), interleukin-6 receptor (IL-6R), calcium (Ca), and magnesium (Mg) in the serum of acute and chronic leukemia patients and healthy subjects.
Materials and Methods
Study Design
This study was carried out in the hematology unit of Baghdad Teaching Hospital/Medical City from November 2020 to January 2021. This study was conducted on a total number of 90 people, of which 30 were healthy subjects (15 males and 15 females) and 60 were leukemia patients (30 males and 30 females). The mean age was 41.53 ± 2.72 years for healthy subjects and 43.48 ± 2.20 years for leukemia patients. The patients were divided into four groups based on their leukemia subtype: 15 with ALL, 15 with AML, 12 with CLL, and 18 with CML. All patients in this study received treatment, and no one was recruited before treatment. The treatment differed according to the type of leukemia. Patients with ALL received chemotherapy and glucocorticoids, and patients with AML received chemotherapy as well. Most chronic leukemia patients were mostly treated with targeted therapies such as ibrutinib in patients with CLL and imatinib in patients with CML. The patients were referred and admitted to the hematology department of Baghdad Teaching Hospital for diagnostic assessment and treatment of their hematological diseases, in which the diagnosis was made by consultant hematologists according to the baseline protocol of the hematology unit. The information was collected from every patient, including age, sex, chronic disease, duration of the disease, type of leukemia, type of treatment, and body mass index (BMI) (Kg/m2). This study excluded patients with thyroid problems, asthma, and arthropathies. The approval of the local ethics committee was obtained.
Sample Collection
Blood specimens were obtained from both leukemia patients and healthy subjects. Intravenously, 5 mL of blood was drawn and placed in a vacuum gel tube. After clotting, serum samples were separated by centrifugation for 20 min (at about 1000× g). The serum was then placed in tiny tubes (Eppendorf tubes) and stored in a deep freeze (− 30 ºC) at the blood bank (Ghazi al-Hariri Surgical Specialties Hospital in Medical City) until analysis. CTX-1, PYD, osteocalcin, and IL-6R were measured by ELISA, as described by the manufacturer (Mybiosource, USA). Calcium and magnesium were measured by the semi-automatic biochemical analyzer humalyzer 2000 as described by the manufacturer (HUMAN Diagnostics, Germany).
Statistical Analysis
The SPSS statistical program (Version/20.0; SPSS Inc., Chicago, IL) was used to analyze the data. T-test was used to determine whether there are any statistically significant differences between the means. Data were presented as (mean ± Standard Error). Pearson's correlation (r-correlation) was used to find the correlations among the parameters. Data were considered as significant (S) at P < 0.05, High significant (H.S) at P < 0.01, and Non-Significant (N.S) at P > 0.05.
Results
The results showed that there were no statistically significant differences in age (years) between 60 leukemia patients (43.48 ± 2.20) and 30 healthy subjects (41.53 ± 2.72). The results also showed that there were no statistically significant differences in body mass index (Kg/m2) between leukemia patients (27.49 ± 0.95) and healthy subjects (28.39 ± 1.04).
Patients with leukemia were classified into four subtypes: ALL, AML, CLL, and CML. CTX-1, PYD, OC, IL-6R, Ca, and Mg levels were measured in leukemia subtypes and healthy subjects. As indicated in Table 1, CLL group showed a significant increase in the bone resorption markers CTX-1 and PYD (P < 0.05 and P < 0.01, respectively), but there was no significant difference in ALL, AML, and CML (P > 0.05) as compared with healthy subjects. OC levels revealed a significant decrease (P < 0.05) in AML and CLL and no significant difference (P > 0.05) in ALL and CML. Serum calcium levels showed a significant decrease (P < 0.05 in ALL, AML, and CML and no difference (P > 0.05) in CLL when compared with healthy subjects. In all leukemia subtypes, there was no significant change (P > 0.05) in serum magnesium levels when compared with healthy subjects (P > 0.05). Serum IL-6R showed a significant decrease (P < 0.05) only in CML group compared with healthy subjects.
Table 1.
Serum levels of bone metabolism markers (Mean ± SE) in leukemia subtypes and healthy subjects
| Parameters | Healthy subjects | ALL | AML | CLL | CML |
|---|---|---|---|---|---|
| CTX-1(ng/mL) | 20.36 ± 0.63 | 21.11 ± 0.84 | 22.68 ± 1.01 | 24.01 ± 1.78* | 21.98 ± 0.86 |
| PYD (ng/mL) | 52.009 ± 4.18 | 63.62 ± 5.91 | 52.98 ± 4.84 | 80.90 ± 5.25** | 59.6 ± 5.51 |
| OC (ng/mL) | 40.79 ± 3.10 | 36.53 ± 3.98 | 29.26 ± 3.59* | 28.58 ± 2.90* | 36.25 ± 2.62 |
| Ca (mg/dL) | 9.22 ± 0.20 | 8.38 ± 0.36* | 8.16 ± 0.43* | 9.05 ± 0.35 | 8.31 ± 0.38* |
| Mg (mg/dL) | 2.44 ± 0.01 | 2.43 ± 0.02 | 2.41 ± 0.02 | 2.44 ± 0.01 | 2.45 ± 0.01 |
| IL-6R (ng/mL) | 15.522 ± 0.39 | 15.09 ± 0 .44 | 14.75 ± 0.70 | 14.67 ± 0 .44 | 14.25 ± 0.49* |
ALL acute lymphoblastic leukemia; AML acute myeloid leukemia; CLL chronic lymphocytic leukemia; CML chronic myeloid leukemia; CTX-1 cross-linked carboxy-terminal telopeptide of type 1 collagen; PYD pyridinoline; OC osteocalcin; Ca calcium; Mg magnesium; IL-6R Interleukin-6 receptor; SE standard error
*significant; **high significant
As indicated in Table 2, leukemia patients were divided into two groups based on their age: those over 50 years old and those under 50 years old. The findings revealed a significant increase (P = 0.006) in magnesium levels in patients aged 50 years or older when compared to those under this age, but no significant changes in CTX-1, PYD, OC, Ca, or IL-6R levels. Furthermore, when leukemia patients were segregated by gender, the results revealed no significant differences in all biomarkers, as indicated in Table 3.
Table 2.
Comparison of parameters between leukemia patients according to age
| Parameters | 50 < Age No = 32 Mean ± SE |
Age ≥ 50 No = 28 Mean ± SE |
P-value | Sig |
|---|---|---|---|---|
| CTX-1 (ng/mL) | 21.8 ± 0.62 | 22.69 ± 0.88 | 0.402 | N.S |
| PYD (ng/mL) | 60.28 ± 3.81 | 64.57 ± 4.94 | 0.498 | N.S |
| OC (ng/mL) | 35.39 ± 2.34 | 30.81 ± 2.49 | 0.188 | N.S |
| Ca (mg/dL) | 8.38 ± 0.28 | 8.50 ± 0.25 | 0.763 | N.S |
| Mg (mg/dL) | 2.41 ± 0.01 | 2.46 ± 0.01 | 0.006 | H.S |
| IL-6R (ng/mL) | 14.69 ± 0.35 | 14.36 ± 0.50 | 0.586 | N.S |
H.S high significant, N.S nonsignificant
Table 3.
Comparison of parameters between leukemia patients according to gender
| Parameters | Males No = 30 Mean ± SE |
Females No = 30 Mean ± SE |
P-value | sig |
|---|---|---|---|---|
| CTX-1 (ng/mL) | 22.40 ± 0.72 | 21.94 ± 0.76 | 0.663 | N.S |
| PYD (ng/mL) | 64.33 ± 3.80 | 60.25 ± 4.83 | 0.510 | N.S |
| OC (ng/mL) | 33.37 ± 2.47 | 29.66 ± 2.71 | 0.317 | N.S |
| Ca (mg/dL) | 8.76 ± 0.26 | 8.12 ± 0.27 | 0.100 | N.S |
| Mg (mg/dL) | 2.42 ± 0.01 | 2.44 ± 0.01 | 0.296 | N.S |
| IL-6R (ng/mL) | 14.58 ± 0.37 | 14.50 ± 0.47 | 0.883 | N.S |
Table 4 shows the correlations among the parameters in leukemia subtypes. CTX-1 was shown to be positively correlated with OC (r = 0.554, P = 0.032 and r = 0.608, P = 0.007, respectively) and IL-6R (r = 0.581, P = 0.029 and r = 0.707, P = 0.002, respectively) in both ALL and CML. The findings also revealed a positive correlation between OC and IL-6R in AML (r = 0.585, P = 0.028), and calcium correlated positively with magnesium in CML (r = 0.552, P = 0.018).
Table 4.
Correlation between serum bone metabolic markers in different types of leukemia
| Parameters | ALL | AML | CLL | CML | ||||
|---|---|---|---|---|---|---|---|---|
| r | P-value | r | P-value | r | P-value | r | P-value | |
| CTX-1 with PYD | 0.029 | 0.919 | 0.102 | 0.753 | 0.049 | 0.909 | − 0.086 | 0.788 |
| CTX-1 with OC | 0.554* | 0.032 | 0.522 | 0.100 | 0.369 | 0.369 | 0.608** | 0.007 |
| CTX-1 with Ca | 0.372 | 0.173 | 0.337 | 0.311 | − 0.223 | 0.595 | 0.240 | 0.337 |
| CTX-1 with Mg | 0.402 | 0.138 | 0.076 | 0.823 | − 0.054 | 0.899 | 0.219 | 0.382 |
| CTX-1 with IL-6R | 0.581* | 0.029 | 0.200 | 0.556 | − 0.115 | 0.752 | 0.707** | 0.002 |
| PYD with OC | 0.406 | 0.134 | − 0.227 | 0.435 | − 0.099 | 0.801 | 0.048 | 0.850 |
| PYD with Ca | 0.123 | 0.662 | − 0.089 | 0.753 | − 0.391 | 0.209 | − 0.165 | 0.514 |
| PYD with Mg | − 0.038 | 0.892 | 0.440 | 0.100 | 0.045 | 0.890 | 0.019 | 0.940 |
| PYD with IL-6R | 0.058 | 0.838 | − 0.194 | 0.507 | 0.597 | 0.118 | 0.288 | 0.263 |
| OC with Ca | 0.127 | 0.652 | − 0.105 | 0.722 | − 0.263 | 0.494 | − 0.071 | 0.778 |
| OC with Mg | 0.167 | 0.551 | − 0.246 | 0.397 | − 0.480 | 0.191 | − 0.072 | 0.778 |
| OC with IL-6R | 0.099 | 0.736 | 0.585* | 0.028 | − 0.145 | 0.732 | 0.285 | 0.268 |
| Ca with Mg | 0.148 | 0.598 | 0.188 | 0.503 | 0.339 | 0.217 | 0.552* | 0.018 |
| Ca with IL-6R | − 0.141 | 0.632 | 0.040 | 0.891 | − 0.066 | 0.876 | 0.217 | 0.402 |
| Mg with IL-6R | 0.286 | 0.322 | − 0.068 | 0.817 | − 0.093 | 0.826 | 0.421 | 0.093 |
*Correlation is significant at the P-value < 0.05 level, **Correlation is significant at P-value < 0.01 level
Table 5 shows the correlations between BMI and age with the parameters in leukemia patients. This study showed that there was no significant correlation of biomarkers with age and BMI, except for magnesium, which showed a positive correlation with age (r = 0.296, P = 0.022).
Table 5.
Correlations between parameters with both body mass index and age in serum leukemia patients
| Correlation between | Pearson correlation (r) | P-value | Sig |
|---|---|---|---|
| CTX-1 and age | 0.263 | 0.060 | N.S |
| PYD and age | 0.093 | 0.481 | N.S |
| OC and age | − 0.090 | 0.509 | N.S |
| Ca and age | 0.088 | 0.506 | N.S |
| Mg and age | 0.296* | 0.022 | S |
| IL-6R and age | 0.048 | 0.732 | N.S |
| CTX-1 and BMI | − 0.111 | 0.434 | N.S |
| PYD and BMI | 0.099 | 0 .455 | N.S |
| OC and BMI | − 0.239 | 0.071 | N.S |
| Ca and BMI | − 0.089 | 0.497 | N.S |
| Mg and BMI | 0.173 | 0.185 | N.S |
| IL-6R and BMI | 0.027 | 0.849 | N.S |
*Correlation is significant at the P-value < 0.05 level, **Correlation is significant at P-value < 0.01 level
Discussion
Leukemic cells invading bone marrow may impact the differentiation of osteoblasts and osteoclasts, eventually leading to changes in physiological bone remodeling [8]. In this study, bone resorption markers CTX-1 and PYD indicated a significant increase in CLL group when compared to healthy subjects. CTX-1 and PYD are collagen breakdown products that are released into the circulation by the action of the enzyme cathepsin K, which is secreted by osteoclasts [11]. Previous studies discovered abnormal expression of receptor activator of nuclear factor kappa-B ligand (RANKL) in a subset of B cell malignancies such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) [8, 12, 13]. RANKL, which is released by osteoblasts, is the main cytokine that promotes the differentiation of osteoclast precursor cells into mature osteoclasts, as well as the activation and survival of mature osteoclasts, which increases bone resorption [13]. This might explain why CLL patients have higher levels of bone resorption markers. The results also revealed that there were no statistically significant differences in serum levels of PYD and CTX-1 in ALL, AML, and CML patients as compared to healthy subjects. This study was agreed with a study by Crofton et al. that observed there were no statistically significant changes in urine PYD levels in children with ALL throughout the initial intensification stage of therapy. On the contrary, the levels were considerably lower during the diagnostic and remission induction stages [14]. Previous research found a slight, temporary rise in osteoclast counts in AML but no substantial increase in bone resorption [15]. These findings agree with our study, as it found that there were no statistically significant differences in bone resorption markers in AML patients. Frisch et al. found no change in serum CTX-1 levels in mice with AML at any stage during disease development [16]. The majority of CML patients in this study were treated with imatinib, a drug that suppresses colony-stimulating factor-1 receptor (c-fms), which is required for osteoclast production and thus reduces bone resorption [17]. Tauer et al. showed no statistically significant differences in serum CTX-1 levels in CML rats treated with imatinib [18]. Another study revealed that urine PYD levels in children with CML are mostly normal, and that there is a significant decrease in some bone resorption markers throughout ongoing imatinib therapy [7]. These findings agree with the current study that found there was no significant increase in bone resorption markers in CML patients.
Osteocalcin levels showed a significant decrease in AML and CLL as compared to healthy subjects. These findings are consistent with prior research that found lower levels of OC in AML [19] and CLL [8] patients compared to healthy subjects. AML is a heterogeneous disease defined by the clonal growth of blasts in the bone marrow [10]. According to Geyh et al., AML cells suppress the osteogenic development of bone mesenchymal stem cells, which give rise to osteoblasts, resulting in a reduction in the number of osteoblasts and decreased OC levels [19]. A similar result in mice by Frisch et al. found that leukemia reduces osteoblasts and causes bone loss via lowering osteocalcin levels [16]. Low OC levels were also found in CLL group in this study. A previous study reported that malignant CLL cells produce a high amount of tumor necrosis factor alpha (TNFα) [20], which influences osteoblast function and maturation by inhibiting the formation of extracellular matrix components (e.g., type I collagen) or by downregulating the expression of OC and alkaline phosphatase (ALP). TNFα also suppresses the expression of RUNX2, which is an important transcription factor in osteogenic differentiation, controlling the production of osteoblast markers such as ALP, osteopontin, and OC [8, 21]. The findings also revealed a reduction in OC levels in ALL and CML patients when compared to healthy subjects, but this difference was not statistically significant. In contrast to earlier research, they observed a considerable reduction in ALL [22] and CML [4] when compared to healthy subjects. Halton et al. revealed that ALL patients had low OC levels upon diagnosis, demonstrating that the leukemic process had an influence on bone turnover [23]. Furthermore, treatment with chemotherapy and high-dose steroids in ALL, as well as tyrosine kinase inhibitors such as imatanib in CML, resulted in further decreases in OC levels [4, 22]. Previous research indicated that serum levels of OC were considerably raised after 3 months of imatinib therapy, with higher levels reverting to normal after 24 months [5]. Another study discovered that high serum OC levels in individuals receiving imatinib therapy were maintained for up to 24 months [24]. Because the duration of patients treated with imatinib differed in our study, this medication may have contributed to elevating certain levels for patients in the early months of treatment, and hence the results did not demonstrate statistically significant changes in serum OC levels in the CML group. The results also revealed a positive correlation between CTX-1 and OC in patients with ALL and CML. This may reflect the effect of both resorption and formation, which may enhance bone maintenance and reduce bone loss in these groups.
Calcium levels showed a significant decrease in ALL, AML, and CML as compared to healthy subjects. The findings of this study corresponded with those of previous studies, which found that calcium levels were lower in ALL, AML [25], and CML [26] patients than in healthy subjects. Patients who have a high “tumor burden” of cancer cells or tumors with quickly proliferating cells, such as acute leukemia or non-Hodgkin’s lymphoma, as well as tumors that respond effectively to therapy, are at risk of developing tumor lysis syndrome (TLS), which can occur when cancer cells discharge their contents into the circulation spontaneously (before cancer therapy) but is more prevalent within a week after initiating chemotherapeutic treatment, resulting in hypocalcemia, hyperuricemia, hyperkalemia, and hyperphosphatemia [27]. Calcium deficiency in ALL can also arise as a result of glucocorticoid therapy, which causes hypercalciuria by raising renal excretion of calcium while reducing intestinal calcium absorption and tubular phosphate reabsorption, leading to a negative calcium balance [3]. Previous studies observed that serum calcium levels were also found to be lower in CML patients receiving imatinib treatment [4, 26]. Hypocalcemia and hypophosphatemia are adverse effects of imatinib therapy that have been linked to drug-mediated alterations in the renal and gastrointestinal processing of calcium and phosphate [5]. However, new evidence reveals that imatinib also targets skeleton cells, increasing calcium and phosphate retention and sequestration in bone, resulting in lower circulating levels of these minerals [5, 7]. The findings also revealed a positive correlation between calcium and magnesium in CML patients. Calcium and magnesium metabolism are inextricably linked since the two ions' intestinal absorption and renal excretion are interdependent [28]. Hypocalcemia is a side effect of imatinib therapy that has been linked to drug-mediated alterations in renal and gastrointestinal calcium processing. A reduction in serum calcium levels stimulates the secretion of parathyroid hormone (PTH) by the parathyroid gland [5], which may affect magnesium levels [28].The results also demonstrated a significant increase in magnesium levels in patients aged 50 years or older when compared to those under this age. In addition, magnesium had a positive correlation with age. This condition might be linked to a decline in renal function, which usually occurs with aging [29].
Serum IL-6R levels in CML patients were found to be significantly decreased. The IL-6 receptor complex is comprised of two polypeptide chains: a ligand-specific receptor (IL-6R) and a signal transducer glycoprotein 130 (gp130) [30]. IL-6 binds to sIL-6R to create IL-6/sIL-6R complexes that are then internalized in target cells [31]. When IL-6 attaches to receptors on pre-osteoclasts, it promotes osteoclastogenesis, which leads to increased bone resorption [32]. The majority of CML patients in the current study were treated with imatinib. Previous researchers found that imatinib treatment reduced IL-6 levels in CML patients compared to untreated patients [33, 34]. This may limit the development of the IL-6/sIL-6R complex, which in turn may reduce bone resorption. Another action of reducing bone resorption by imatinib can be explained by the results of O’Sullivan et al. [6] and Berman et al. [35]. Serum IL-6R showed a dual effect, as it was positively correlated with the bone formation marker OC in AML and with the bone resorption marker CTX-1 in ALL and CML. sIL-6R can reduce osteoblastic differentiation by lowering the expression of osteoblastic differentiation genes such as ALP, Runx2, and OC [32]. Previous research has implicated IL-6/sIL-6R as a crucial modulator in the regulation of osteoclastogenesis and bone resorption [36]. In vitro results show that neither IL-6 nor sIL-6R alone can trigger osteoclast development [37]. As a result, more research is needed to determine the role of serum IL-6R in modifying bone metabolism since sIL-6R in the serum is inert due to its binding in a ternary complex with soluble gp130 and IL-6.
Limitation of the Study
The small sample size and study time were limited; there was also no follow-up for the patient, and there was difficulty in obtaining the sample.
Conclusion
Changes in bone turnover markers were reported in this study, with resorption enhanced and formation reduced or unchanged in leukemia subtypes. These changes can be caused by leukemias and antileukemic agents. More bone loss is detected in CLL patients because they have high bone resorption markers (CTX-I and PYD) and low bone formation markers (OC). Low OC levels have also been seen in AML patients, indicating bone loss owing to the inhibition of mature osteoblasts and decreased bone formation. Treatment modalities (chemotherapy in ALL and AML, Imatinib in CML) may reduce serum calcium levels. Imatinib has also been found to play a role in reducing bone resorption markers and reducing bone loss in CML patients. We suggest that these indicators are important as predictors of bone abnormalities in patients with leukemia.
Acknowledgements
We would like to thank all the participants in this research study, including patients, healthy subjects, the staff of the hematology unit at Baghdad Teaching Hospital and the staff of the blood bank at Ghazi al-Hariri Surgical Specialties Hospital in Medical City, for their cooperation. Also, we are grateful to the Applied Chemistry Branch, Department of Applied Science, University of Technology for providing facilities.
Author Contributions
RAA assisted in the study design, data collection, analysis, and interpretation, manuscript writing, and statistical analysis. AMA and MHMA designed the study, assisted with data collection, analysis, and interpretation, oversaw the project, gave advice and direction, and contributed to manuscript preparation. All authors approved the final version of the manuscript submitted.
Declarations
Conflicts of interest
All the authors have no conflict of interest to declare.
Consent to Participate
All participants agreed to this study, and the approval of the local ethics committee was obtained. There was no specific picture or information we wanted to publish in this manuscript.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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