|Year : 2019 | Volume
| Issue : 4 | Page : 218-226
Leukocyte-associated immunoglobulin-like receptor-1, T-cell leukemia/lymphoma protein-1, and nuclear factor κB expression in childhood acute lymphoblastic leukemia
Mona H.Y Alrayes1, Reham H.M Hammad1, Botheina A.T Farweez2, Nayera H.K Elsherif3, Doaa A.A Aly MSc 1
1 Department of Clinical Pathology, Faculty of Medicine (for Girls), Al-Azhar University, Cairo, Egypt
2 Department of Clinical Pathology, Faculty of Medicine Ain Shams University, Cairo, Egypt
3 Department of Pediatrics, Faculty of Medicine Ain Shams University, Cairo, Egypt
|Date of Submission||23-Jan-2019|
|Date of Acceptance||21-Mar-2019|
|Date of Web Publication||20-Jul-2020|
Doaa A.A Aly
235, Abd El-Gelel El-Behery Street, Hadaeq El-Qobba, Cairo
Source of Support: None, Conflict of Interest: None
Background Immune regulation is crucial for the pathogenesis of childhood acute lymphoblastic leukemia (ALL). Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is an immune regulator, expressed by T and B immune cells. T-cell leukemia/lymphoma protein-1 (TCL1) is a coactivator of α-serine/threonine-protein kinase, and when dysregulated, it causes lymphomagenesis and cancer progression. Nuclear factor-κB (NF-κB) is a transcription factor that regulates genes involved in immune responses. This study aimed to study the expression of LAIR-1, TCL1, and NF-κB on blasts in childhood ALL with evaluation of their prognostic value.
Patients and methods This descriptive cross-sectional study was conducted on 60 newly diagnosed childhood ALL cases. They were divided into group 1 (n=47) of B-cell ALL and group 2 (n=13) of T-cell ALL. The expression pattern of LAIR-1, TCL1, and NF-κB on blasts was assessed using flow cytometry.
Results Correlation studies in total patients with ALL (n=60) revealed significant positive correlation between percentage of blasts expressing LAIR-1% and total leukocytic count (r=0.262, P=0.043) and percentage of blasts infiltrating the peripheral blood (r=0.292, P=0.025). A significant positive correlation of LAIR-1 mean fluorescence intensity with percentage of blasts expressing CD13 (r=0.293, P=0.026) and CD33 (r=0.373, P=0.004) was found. In group 2, a significant positive correlation was seen between percentage of blasts expressing TCL1 and LAIR-1 mean fluorescence intensity (r=0.566, P=0.044). According to Cox regression analysis, the percentage of blasts expressing NF-κB was seen to significantly increase the risk of death, in childhood ALL (hazard ratio=1.085, 95% confidence interval=1.02–1.16, P=0.01).
Conclusion LAIR-1 expression carries the potentiality of being a bad prognostic marker in childhood ALL. A relation is suggested between the expression of both LAIR-1 and TCL1 on blasts. NF-κB expression might negatively influence the survival rate in childhood ALL.
Keywords: childhood acute lymphoblastic leukemia, flow cytometry, leukocyte-associated immunoglobulin-like receptor-1, nuclear factor-κB, T-cell leukemia/lymphoma protein-1
|How to cite this article:|
Alrayes MH, Hammad RH, Farweez BA, Elsherif NH, Aly DA. Leukocyte-associated immunoglobulin-like receptor-1, T-cell leukemia/lymphoma protein-1, and nuclear factor κB expression in childhood acute lymphoblastic leukemia. Egypt J Haematol 2019;44:218-26
|How to cite this URL:|
Alrayes MH, Hammad RH, Farweez BA, Elsherif NH, Aly DA. Leukocyte-associated immunoglobulin-like receptor-1, T-cell leukemia/lymphoma protein-1, and nuclear factor κB expression in childhood acute lymphoblastic leukemia. Egypt J Haematol [serial online] 2019 [cited 2021 Nov 28];44:218-26. Available from: http://www.ehj.eg.net/text.asp?2019/44/4/218/290235
| Introduction|| |
Childhood acute lymphoblastic leukemia (ALL) comprises ∼30% of malignancies in childhood . In Egypt, the annual incidence of childhood ALL is approximately four cases per 100 000 children .
Immune regulation is crucial for the pathogenesis of ALL. Prosurvival signals provided by tissue microenvironments, such as crosstalk between B-cell acute lymphoblastic leukemia (B-ALL) cells and CD4+ T cells, and mesenchymal stromal cells, contribute toward maintaining leukemic clones and promoting chemotherapy resistance .
Leukocyte-associated immunoglobulin (Ig)-like receptor-1 (LAIR-1) (CD305) is an immune regulator that is widely expressed by most immune cells, including T cells, B cells, monocytes, and CD34+ hematopoietic progenitors. LAIR-1 contributes to the regulation of the immune system by delivering inhibitory signals .
T-cell leukemia/lymphoma protein-1 (TCL1) is a ∼14 kDa protein that belongs to the TCL1 protein family. TCL1 acts as a coactivator of α-serine/threonine-protein kinase, and when physiologically expressed, it mediates normal growth and survival signals, whereas when dysregulated, it causes lymphomagenesis and cancer progression. TCL1 regulates many proteins responsible for cellular proliferation, survival, and epigenetic regulation through multiple signaling pathways. TCL1 enhances the activation of the nuclear factor κB (NF-κB) pathway by direct actions on inhibitor of NF-κB α and ataxia telangiectasia mutated .
NF-κB is a transcription factor; its action encompasses activation, proliferation of the innate and adaptive immune cells, and organogenesis of lymphoid tissue . Constitutive expression of NF-κB has been associated with several types of cancer, and also the multifactorial role of NF-κB as a cancer driver has been confirmed .
This work aimed to study the expression of LAIR-1, TCL1, and NF-κB on blasts in childhood ALL using flow cytometry in newly diagnosed patients to evaluate their prognostic value and their relation to patient’s treatment response.
| Patients and methods|| |
This descriptive cross-sectional study was conducted on 60 childhood ALL cases of both B-cell and T-cell types. The patients were recruited from the inpatients of the Pediatric Oncology Unit, Ain Shams University, during the period between June 2016 and June 2017. Patients were followed up till June 2018. Written consents were taken from patients’ parents before proceeding the study. The study procedure was approved by the Local Ethical Committee of the Faculty of Medicine, Al-Azhar University.
All study participants were subjected to full history taking, clinical examination, and laboratory investigations including complete blood pictures by Sysmex KX21 (Hematology analyzer; Sysmex Corporation, Kobe, Japan); examination of blood films for assessment of blasts (%); and bone marrow (BM) examination for (i) morphology, (ii) cytogenetic studies, and (iii) immunophenotyping of blasts using standard leukemia panel. Cells were considered positive for a certain marker when at least 20% of cells expressed it, except for CD34, where 10% was sufficient to confer positivity.
Newly diagnosed children with ALL below the age of 18 years before initiating therapy were included. Diagnosis of ALL was confirmed by the presence of 20% or more blasts in the BM films according to the WHO proposal, together with MPO negative staining and immunophenotyping results consistent with ALL . Exclusion criteria were patients with ALL who started treatment, patients in relapse, and patients with acute myeloid leukemia.
Patients were followed up during the period of treatment. Treatment response was assessed according to the Total XV Protocol of treatment. The minimal residual disease (MRD) was done by flow cytometry based on the initial results at days 19 and 42. The cutoff value of MRD is 0.01% . Conventional and fluorescence in-situ hybridization cytogenetic studies were done to the patients on the initial BM samples for ALL-associated translocations. Unfavorable cytogenetic abnormalities included hypodiploidy, t(1:19), Philadelphia-chromosome (BCR-ABL)-positive ALL, and E2A-PBX1 fusion or MLL rearrangement . Complete remission was achieved when white blood cells were at least 3×109/l, with normal differential count; BM is normocellular (with normal differential count or <5% blasts); MRD is less than or equal to 0.01%; and all clinical and laboratory manifestations of acute leukemia should be absent.
Immunophenotyping was performed on 2 ml of BM sample transferred to heparin tube before the administration of any treatment. The samples were analyzed within 24 h of collection for assessment of LAIR-1, TCL1, and NF-κB using flow cytometry.
Flow cytometry was conducted at the Clinical Pathology Department, Al-Zahraa University Hospital, Al-Azhar University, using four colors FACS Calibur (BD, Biosciences, San Jose, California, USA). Cell Quest Pro software (BD Biosciences) was used for data analysis. Compensation setting was established before acquiring the samples using color calibrite beads (lot no. 5093879; BD Biosciences). After adjusting the sample count for acquisition, 50 μl of adjusted sample was added to four tubes.
Tube A for isotype controls, mouse IgG2a PE control (cat. no. 342409) and mouse IgG APC-control (cat. no. 550931), was obtained from BD Biosciences for detection of nonspecific binding of surface LAIR and intracytoplamic TCL1, after following intracytoplamic staining procedure as tube C.
Tube B for isotype controls, mouse IgG1 FITC control (cat. no. 342409), was obtained from BD Biosciences for detection of nonspecific binding of intranuclear NF-κB after following the same intranuclear staining procedure as tube D.
Tube C was used for detection of both surface expression of LAIR-1 by PE conjugated Ab (Cat. no. 550811, Lot no. 5329747; BD Biosciences) and intracellular expression of TCL1 by APC-conjugated monoclonal antibody (cat. no 130-104-134. Lot no: 5160616139; Miltenyi Biotec Inc., GmbH, Bergisch Gladbach, Germany). This was done starting with surface staining of LAIR-1, then fixation using 1 ml of 2% formaldehyde solution for each tube, then incubation at room temperature (19°–25°C) for 10 min followed by permeabilization by adding 10 µl of Tween20 solution in 1 ml PBS for each tube for another 10 min, and then centrifugation before adding APC-conjugated TCL1 antibody. The cutoff value of positivity of LAIR-1 was 30% as suggested by Perbellini et al. .
Tube D was used for detection of expression of intranuclear NF-κB by antihuman FITC conjugated monoclonal antibody (cat. no.130-107-834. Lot. no 5160616142; Miltenyi Biotec Inc.). Staining of intranuclear NF-κB was done after fixation of cells by adding 1 ml of 2% formaldehyde incubated at room temperature (19°–25°C) for 10 min followed by permeabilization by slowly adding 1 ml of ice-cold (−20°C) methyl alcohol 99.5% for each tube (Harsh permeabilization method).
The optimal concentration for each antibody dye used was detected by titration experiments in all diagnostic and research markers.
Using forward and side scatter, initial gating was performed on blasts area in the dot plot graph; then within the blast population, the subsets of cells expressing LAIR-1, TCL1, and NF-κB were determined and their percentage evaluated on quadrant histogram. Acquisition was set to 50 000 cells. Determining positive cutoff was done using isotype control. In tube C, LAIR-1 was determined on x-axis, whereas TCL1 was determined on y-axis, and the area of coexpression was determined on upper right quadrant. In tube D, NF-κB was detected on x-axis ([Figure 1]). Data were also expressed as mean fluorescence intensity (MFI) of LAIR-1, TCL1, and NF-κB using single histogram ([Figure 2]).
|Figure 1 Tubes A and B: isotype control. Tube C: LAIR/TCL1; expression of LAIR-1 PE represented on x-axis versus TCL1 APC on y-axis. Tube D: NF-κB; expression of NF-κB FITC represented on x-axis in a case of childhood acute lymphoblastic leukemia. LAIR-1, leukocyte-associated immunoglobulin-like receptor-1; NF-κB, nuclear factor κB; TCL1, T-cell leukemia/lymphoma protein-1.|
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|Figure 2 MFI of LAIR-1-positive, TCL1-positive, and NF-κB-positive blasts using a single histogram initially gated on blasts (R1). MFI of each was measured in area under M1 marker. LAIR-1, leukocyte-associated immunoglobulin-like receptor-1; MFI, mean fluorescence intensity; NF-κB, nuclear factor κB; TCL1, T-cell leukemia/lymphoma protein-1.|
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Data were coded and entered using the statistical package for the social sciences, version 25. Data were coded and entered using the statistical package for the Social Sciences (SPSS) version 25 (IBM Corp., Armonk, NY, USA). Data were summarized using mean, SD, median, minimum, and maximum in quantitative data and using frequency (count) and relative frequency (%) for categorical data. Comparisons between quantitative variables were done using the nonparametric Mann–Whitney test. For comparing categorical data, χ2-test was performed. Exact test was used instead when the expected frequency is less than 5. Cox regression procedure is used for modeling the time to a specified event. P values less than 0.05 were considered as statistically significant.
| Results|| |
In this study, of the recruited patients with ALL, 47 had B-ALL and 13 had T-cell acute lymphoblastic leukemia (T-ALL). Demographic data of the patients are illustrated in [Table 1]. Clinical data are illustrated in [Table 2]. Blood parameters and study parameters of B-ALL and T-ALL cases are illustrated in [Table 3].
|Table 1 Demographic data of the B-cell acute lymphoblastic leukemia and T-cell acute lymphoblastic leukemia cases|
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|Table 2 Clinical data of B-cell acute lymphoblastic leukemia and T-cell acute lymphoblastic leukemia cases|
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|Table 3 Comparison between B-cell acute lymphoblastic leukemia and T-cell acute lymphoblastic leukemia cases regarding blood and study parameters|
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B-ALL cases were subdivided according to cytogenetic studies into B-ALL with unfavorable cytogenetic abnormality (n=11), B-ALL with favorable cytogenetic abnormality (n=12), and B-ALL with normal cytogenetic (n=18).
This study reported that median value of total leukocyte count (TLC) in T-ALL cases was significantly higher than in B-ALL cases (P=<0.001). Moreover, comparison of peripheral blood (PB) blasts (%) revealed higher infiltration in T-ALL cases (P=0.001) ([Table 3]).
The frequency of aberrant myeloid marker expression in this study showed that in children with B-ALL, CD13 was expressed in 20% of cases, CD33 was expressed in 20% of cases, and CD13/CD33 coexpression was seen in 33.3%. However, in T-ALL cases, CD13 was expressed in 33.3% of cases, CD33 was expressed in 66.7% of cases, but no coexpression of CD13/CD33 was seen.
Comparison of percentage of blasts expressing LAIR-1, TCL1, and NF-κB in B-ALL cases and T-ALL cases revealed no statistical significance (P=0.278, 0.190, 0.843, respectively). Moreover, comparison of MFI of LAIR-1, TCL1, and NF-κB between B-ALL cases and T-ALL cases revealed no statistical significance (P=0.080, 0.233, and 0.315, respectively) ([Table 3]).
Comparison of the study parameters between B-ALL cases with unfavorable cytogenetic abnormality and B-ALL with favorable cytogenetic abnormality revealed that NF-κB MFI is significantly decreased in B-ALL with unfavorable cytogenetic abnormality (P=0.044) ([Figure 3]). However, the percentage of blasts expressing NF-κB is decreased in B-ALL with unfavorable cytogenetic abnormality but with no statistical significance (P=0.091).
|Figure 3 Mean value of NF-κB MFI in group 1a (B-cell acute lymphoblastic leukemia with unfavorable cytogenetic abnormality) and group 1b (B-cell acute lymphoblastic leukemia with favorable cytogenetic abnormality). MFI, mean fluorescence intensity; NF-κB, nuclear factor κB.|
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Comparison of blood parameters between B-ALL with unfavorable cytogenetic abnormality and B-ALL with normal cytogenetic revealed significant increase in frequency of CD33 in B-ALL with normal cytogenetic with median values of 2.00 and 3.90, respectively (P=0.044). However, the comparison of MRD results regarding day 42 by flow cytometry revealed significant increase in blasts in B-ALL with unfavorable cytogenetic abnormality with median values of 0.17 and 0.01, respectively (P=0.018).
Comparison of blood parameters between B-ALL with favorable cytogenetic abnormality and B-ALL with normal cytogenetic revealed significant increase in BM blasts percentage in B-ALL with favorable cytogenetic abnormality (P=0.031).
Correlation studies in total patients with ALL (n=60) revealed significant positive correlation between percentage of blasts expressing LAIR-1 and both TLC (r=0.262, P=0.043) and percentage of blasts infiltrating PB (r=0.292, P=0.025) ([Figure 4]). Significant positive correlation of LAIR-1 MFI with percentage of blasts expressing CD13 (r=0.293, P=0.026) and CD33 (r=0.373, P=0.004) was detected. Significant positive correlation of percentage of blasts expressing LAIR-1 and percentage of BM blasts in day 19 of MRD after chemotherapy (r=0.311, P=0.045) ([Figure 5]) was found.
|Figure 4 Correlation studies in total acute lymphoblastic leukemia cases illustrate a significant positive correlation of percentage of blasts expressing LAIR-1 with percentage of PB blasts (a), TLC (b) and with percentage of BM blasts day 19 MRD (c). BM, bone marrow; LAIR-1, leukocyte-associated immunoglobulin-like receptor-1; MRD, minimal residual disease; PB, peripheral blood; TLC, total leukocyte count.|
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|Figure 5 Correlation studies in total acute lymphoblastic leukemia cases illustrate a significant positive correlation of LAIR-1 MFI with percentage of blasts expressing CD13 (a) and with percentage of blasts expressing CD33 (b). LAIR-1, leukocyte-associated immunoglobulin-like receptor-1; MFI, mean fluorescence intensity.|
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In T-ALL cases, there was significant positive correlation of percentage of blasts expressing TCL1 and LAIR-1 MFI (r=0.566, P=0.044).
According to Cox regression analysis, the percentage of blasts expressing NF-κB was seen to significantly increase the risk of death in childhood ALL (hazard ratio=1.085, 95% confidence interval=1.02–1.16, P=0.01).
| Discussion|| |
Leukemia is the most prevalent pediatric malignancy with ALL accounting for 75% of leukemia cases . Regulation in adaptive immune response balances a fine line that prevents abnormal cell growth in leukemia .
This study showed that the incidence of B-ALL was higher (78.3%) than T-ALL which was only 21.6%. This was in agreement with Ibagya et al.  who reported higher incidence of B-ALL in cases of childhood ALL.
Mean value of age in B-ALL cases and T-ALL cases was higher than mean value of age reported by most researchers who reported lower mean value of age in ALL, with the peak incidence occurring at 3–5 years of age ,.
This study showed that in B-ALL cases, the male: female ratio was 1.13 : 1, whereas in T-ALL cases, the male: female ratio was 12 : 1, which indicates higher male incidence in T-ALL. Similar findings were reported by Mitchell et al.  and You et al. .
Assessment of aberrant expression of myeloid markers in this study showed that CD13 was expressed in 20% of cases, CD33 was expressed in 20% of cases, and CD13/CD33 coexpression was seen in 33.3% in B-ALL cases. However, in T-ALL cases, CD13 was expressed in 33.3%, CD33 was expressed in 66.7%, whereas no coexpression of CD13/CD33 was seen. Lopes et al.  stated that CD13 and CD33 were the most frequently detected aberrant myeloid markers expressed in ALL. Mazher et al.  and Suggs et al.  reported higher frequency of expression of aberrant myeloid markers in T-ALL. In contrast, lower frequencies of aberrant myeloid marker expression were identified by Bhushan et al.  and Shen et al. , with 23, and 27%, respectively. The conflict in reports about the incidence of aberrant antigen expression in childhood ALL might be owing to the variation in the sensitivity and/or specificity of the monoclonal reagents used, the use of different cutoff values, and differences in phenotypic characterization of leukemic cells in adult and children .
Importance has been given for the expression of CD13 and CD33 on leukemic lymphoblasts because they have been associated with inferior complete remission (CR) rate . Dalal et al.  suggested that patients with standard-risk (SR)-ALL with aberrant expression of CD13 should be considered for more aggressive management.
The TLC at diagnosis is one of the strongest independent predictors of induction failure and risk of relapse in childhood ALL and accordingly has been used for treatment stratification ,,. This study reported that the median value of initial TLC in T-ALL cases was significantly higher than in B-ALL cases (P<0.001) ([Table 3]). Similar finding was reported by Vaitkeviciene et al. . Moreover, comparison of PB blasts (%) revealed higher infiltration in T-ALL cases (P=0.001) ([Table 3]). These results might reflect the worse prognosis of T-ALL cases than B-ALL.
Comparison between B-ALL and T-ALL regarding the studied parameters revealed no significant differences. The NF-κB MFI was significantly decreased in B-ALL with unfavorable cytogenetic abnormalities when compared with B-ALL with favorable cytogenetic abnormalities (P=0.044). This finding could indicate that NF-κB plays a good prognostic role in B-ALL. Pires et al.  reported that in childhood ALL, NF-κB is constitutively expressed in most cases, independent of the subtype. Different results were reported by Tao et al. . They found that NF-κB mRNA expression levels and the protein level were higher in the high-risk group than in the standard-risk group of patients with B-ALL. They also added that NF-κB levels were upregulated at the newly diagnosed stage of ALL and then were decreased to lower level or even undetectable at the complete remission stage. NF-κB expression levels increased again after disease relapse. Thus, NF-κB may serve as a promising indicator of B-ALL progression and predict the treatment response.
In this study, there was a significant increased expression of myeloid marker CD33 in patients with B-ALL with normal karyotyping when compared with patients with unfavorable cytogenetic abnormalities (P=0.044). Different data were obtained by Emerenciano et al. . They proved an association between unusual aberrant expressions of a myeloid marker with chromosomal translocations in patients with ALL.
Comparison of MRD results regarding day 42 by flow cytometry revealed significant increase in blasts in patients with B-ALL with unfavorable cytogenetic abnormalities than in patients with B-ALL with normal cytogenetic (P=0.018). Pui et al.  and Bhojwani et al.  proved that patients who have a rapid reduction in leukemia cells were found to have a more favorable prognosis than patients who have slower clearance of leukemia cells from BM.
Correlation studies in total patients with ALL revealed a significant positive correlation of percentage of blasts expressing LAIR-1 and both TLC (P=0.043) and percentage of PB blasts (P=0.025) ([Figure 4]). Previously, Crazzolara et al.  reported that such extramedullary presentation of blasts indicates a bulk of ALL cells trafficking outside the BM which correlates with inferior prognostic importance. The finding of this study might throw spotlight on the bad prognostic role of LAIR-1 in ALL.
There was a significant positive correlation between LAIR-1 MFI and both myeloid markers CD13 (%) (P=0.026) and CD33 (%) (P=0.004) in total ALL cases. These data could throw light on the prognostic importance of LAIR-1 in childhood ALL. Bhushan et al.  stated that immunophenotyping analysis of aberrant marker expression is useful for the prognostic evaluation of children with ALL and used as bad prognostic indicators. Dalal et al.  reported that aberrant expression of CD13 identifies a subgroup of standard-risk adult ALL with inferior survival.
In this study, there was a significant positive correlation between percentage of blasts expressing LAIR-1 and percentage of BM blasts at day 19 of MRD detection after chemotherapy (P=0.045) in total ALL cases. Hunger and Mullighan  reported that the risk of treatment failure and death was to be three to five times more among children with levels of MRD more than 0.01 than among those with lower than 0.01% at day 19. This strengthens the potentiality of LAIR-1 as bad prognostic factor in childhood ALL.
In T-ALL cases, there was a significant positive correlation between percentage of blasts expressing TCL1 and LAIR-1 MFI (r=0.566, P=0.044), whereas there was a significant negative correlation between LAIR-1 MFI and NF-κB MFI (r=−0.61 and P=0.027), suggesting integrating relations among these markers in leukemic lymphoblasts.
According to Cox regression analysis, the percentage of blasts expressing NF-κB was seen to significantly increase the risk of death, in childhood ALL, with hazard ratio of 1.085. Tao et al.  reported that NF-κB mRNA expression levels were higher in the high-risk group than in the standard-risk group.
| Conclusion|| |
(i) LAIR-1 expression carries the potentiality of being a bad prognostic marker in childhood ALL being correlated to independent bad prognostic factors. (ii) A relation is suggested between the expression of both LAIR-1 and TCL1 on blasts of childhood ALL. (iii) NF-κB expression might negatively influence the survival rate in childhood ALL.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]