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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 7  |  Issue : 3  |  Page : 109-116

Study of the association of phosphatase and tensin homolog and p27 expressions in endometrial hyperplasia and carcinoma


Department of Pathology, Faculty of Medicine, Assuit, Al-Azhar University, Egypt

Date of Web Publication30-Aug-2019

Correspondence Address:
Dr. Ihab Shafek Atta
Department of Pathology, Faculty of Medicine, Assuit, Al-Azhar University
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JMAU.JMAU_54_18

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  Abstract 


Introduction: Phosphatase and tensin homolog (PTEN) and p27 are commonly mutated gene in endometrial carcinoma (EC) and their association in development of EC has not been fully understood. The Aim of the Study: The aim is to clarify the association of PTEN and p27 in EC and their correlation with the histologic grade. Material and Methods: Paraffin-embedded 20 and 50 specimens representing EH and EC were collected, cut into 4 mm thick and stained with H&E stain for histopathological examination. All EC cases were graded according to the percentage of nonsquamous solid pattern into 3 grades. Immunohistochemical (IHC) analyses were done using a rabbit polyclonal anti-PTEN antibody and a rabbit monoclonal anti-p27 antibody. Evaluation of reactivity was categorized: 1+ (weak) = less than 10%, 2+ (moderate) = 11 to 50% and 3+ (strong) = more than 50% tumor. t-test, one way ANOVA and chi-square test were used in the statistical analysis. Results: Loss of PTEN was seen in 7/20 (35%) and 29/50 (58%) of EH and EC cases with significance (P =0.01824), opposite to 17/20 (85%) and 25/50 (50%) of p27 (P = 0.00334). Both antibodies showed significance in EH cases only (P= 0.00019). No correlation with the histological grade for both antibodies. Four major categories were formulated; PTEN+/p27+ (n= 2, 14, 10%, 28%), PTEN+/p27- (n = 5, 7; 25% and 14%), PTEN-/p27+ (n= 1, 11; 5%, 22%) PTEN-/p27- (n= 12, 18; 60%, 36%) cases of EH and EC, respectively with no significant difference obtained. Conclusion: Not all cases of PTEN negative EC showing p27 loss and vice versa. Despite many studies reacted with PTEN and p27 expression in EC, none of them is confirmatory to adjust the correlation between them in EC. So, more studies must be done to correlate between the degree of PTEN loss and p27 comprising all subtypes and grading of EC.

Keywords: Endometrial carcinoma, endometrial hyperplasia, endometrium, p27, phosphatase and tensin homolog


How to cite this article:
Atta IS. Study of the association of phosphatase and tensin homolog and p27 expressions in endometrial hyperplasia and carcinoma. J Microsc Ultrastruct 2019;7:109-16

How to cite this URL:
Atta IS. Study of the association of phosphatase and tensin homolog and p27 expressions in endometrial hyperplasia and carcinoma. J Microsc Ultrastruct [serial online] 2019 [cited 2019 Nov 14];7:109-16. Available from: http://www.jmau.org/text.asp?2019/7/3/109/256308




  Introduction Top


Endometrial carcinoma (EC) is reported as the fourth most common cancer of women worldwide and is considered one of the most common malignancies affecting the female genital tract.[1] However, its molecular carcinogenesis has not been fully understood. Phosphatase and tensin homolog (PTEN) is the most commonly mutated gene recognized in EC and is one of a tumor suppressor genes, which mapped on 10q23, and modifications of this gene have been recognized in a wide variety of cancers together with EC.[2],[3] PTEN is a lipid phosphatase which acts as dephosphorylating agent on the subsequent messenger of P13K2 through the cascades of phosphatidylinositol 3, 4, 5-triphosphate.[2],[4] The 30%–50% PTEN mutations' prevalence in EC ranks at the top of analyzed tumors.[5] Furthermore, the mutations were discovered in about 20% of cases of endometrial hyperplasia (EH), an antecedent of EC.[6] Therefore, the PTEN inactivation is measured to be the early episode in endometrial carcinogenesis.

Multiple lines of evidence support a role for the PTEN as one such marker for EC. The potential role of PTEN is to inhibit some tumor suppressor genes such as p27, p53, and p21 by producing a second messenger for the AKT pathway.[3] It also regulates proliferation, growth, and apoptosis in a phosphatidylinositol 3-kinase (PI3K)-dependent pathway.[2],[7] Finally, to antagonize the action of PI3K activity through inhibition of its downstream target; serine/threonine kinase AKt.[8] Phosphorylated-activated Akt adjusts the activity of a diversity of downstream protein cascades that narrate to cell proliferation and survival.[1] The activated Akt phosphorylates followed by inactivation of the proapoptotic factor as Bax suppresses the apoptotic process and hence promotes cell survival and proliferation.[9],[10] PTEN inactivation associated with activation of PI3K together will give rise to AKT phosphorylation, as well as accumulation of beta-catenin in nuclei, and hence, activation of gene transcription occurs.[11]

Alternatively, the PTEN overexpression hinders cell growth and encourages a G1 arrest with augmenting the cell cycle kinase inhibitor p27,[12],[13] signifying that PTEN inactivation consequences may lead to cell cycle progression via downregulation of p27. Hence, the loss of PTEN function with subsequent activation of PI3K and Akt/protein kinase B signaling pathway plays a considerable role in the pathogenesis of cancer. However, those conclusions are somewhat less obvious, poorly understood and have to be clarified more in EC. Loss of PTEN expression in mice gives rise to both EH and EC.[14],[15] Furthermore, mutations in PTEN have been found in patients with Cowden syndrome.[16]

On the other hand, the cell cycle regulator and tumor suppressor p27 play a key role in the development of EC. p27 is a member of the cyclin-dependent kinase interacting protein/kinase inhibitory protein (Cip/Kip) family of cyclin-dependent kinase inhibitors (CKIs), which function to negatively regulate cell cycle progression.[17] The cell cycle and phosphorylation-dependent events that control p27 levels and subcellular localization are catalyzed by different kinases that regulate degradation and nuclear-cytoplasmic shuttling. Nuclear p27 is targeted for degradation by Skp2 E3 ligase.[18] Phosphorylation of p27 by several kinases including AKT causes nuclear p27 to be exported to the cytoplasm.[19],[20] In the cytoplasm, p27 is targeted for degradation by a different E3-ligase.[21] In addition to targeting p27 for degradation, phosphorylation also can stabilize this CKI and sequester it in the cytoplasm. In the cytoplasm, p27 has been shown to and mediate cell migration and metastasis by blocking Rho stress fiber formation[22],[23],[24] and be antiapoptotic.[25] Dysregulation of p27 has been reported in EC, most commonly as a result of the decreased p27 expression.[26],[27],[28] During the progression of EC, normal regulation of p27 is lost, with p27 being absent or undetectable in a significant proportion of EH.[29] Alternatively, p27 expression in some EC is expressed in the cytoplasm.[30] In addition to aberrant p27, alterations in the PTEN tumor suppressor and other cell cycle regulators signaling pathway comprise the important mutation group for development of EC.[31],[32]

Although many studies reacted with PTEN and p27 expression in EC, none of them is confirmatory to adjust the correlation between them in EC. Hence, the aim is to stand on the accurate expression of both antibodies in EC, to find a correlation with the histological grade, and to detect the extent of their association and correlation in EC cases.


  Materials and Methods Top


Paraffin-embedded 20 and 50 archival specimens representing EH and EC were collected from the Department of Pathology, Al-Azhar University Hospitals, and from some private laboratories after following the ethical guidelines and obtaining the written permission. These specimens were collected from the period between 2010 and 2017. All specimens were cut into 4-mm thick sections and stained with H and E stain for histopathological examination.

All EC cases were classified according to the International Federation of Gynecology and Obstetrics (FIGO)[33] criteria based on the percentage of nonsquamous or nonmorular solid pattern; Grade 1: <5%, Grade II: 6%–50%, and Grade 3: >50%.

For immunohistochemical (IHC) analyses, the tissue sections were cut at 4 μm and mounted on poly-L-lysine-coated slides. IHC for PTEN was done using a rabbit polyclonal anti-PTEN antibody, ab31392 (Abcam, Cambridge, UK) at a concentration of 100 μg at 1 mg/ml. p27 was done using a rabbit monoclonal anti-p27 antibody KIP 1, ab32034 (Abcam, Cambridge, UK) at a concentration of 100 μg at 0.52 mg/ml.

The staining procedure was automated and consisted of incubation for 45 minutes with the primary antibody, then washed by a brief buffer followed by an incubation with biotinylated anti-mouse IgG/IgM (Abcam, Cambridge, UK) for thirty minutes. The slides were subsequently incubated with avidin/biotin (Abcam, Cambridge, UK) for 30 minutes and reacted with diaminobenzidine (DAB) and hydrogen peroxide (H2O2). The sections were counterstained with hematoxylin. Evaluation of staining reactivity was done and any degree of brownish nuclear PTEN and nuclear/cytopasmic p27 reactivity were considered as a positive.[19],[20] The percentage of positive cells were calculated and the staining category was graded as follows: 1+ (weak) = less than 10% of cells are stained positive, 2+ (moderate) = 11 to 50% of the stained cells are positive, and 3+ (strong) = more than 50% tumor cells stained positive.[34],[35],[36],[37]

t-test was used to compare the degree of reactivity between the two lesions (EH and EC) for PTEN and p27 in a separate manner. Also, one way ANOVA test was used to compare the degree of PTEN and p27 reactivity data with the histological FIGO grading. Chi-square test was used to measure the extent of association of the two antibodies in both endometrial hyperplasia and carcinoma cases (positive PTEN/ positivep27, positive PTEN/negative p27, negative PTEN/ and positive 27, and negative PTEN/negative p27). All P values were two-sided. P ≤ 0.05 was considered statistically significant. Computer software Statistical Package for the Social Science (SPSS) version 16 (Statistics for Windows, IBM Corp., Armonk, N.Y., USA) was used in the analysis of the current study.


  Results Top


Staining of the 20 cases of EH with anti-PTEN antibody revealed that 7/20 (35%) showed negative staining, weak in six (30%), moderate in four (20%), and strong in three (15%) cases [Figure 1] and [Figure 2]. Regarding EC, loss of PTEN expression or negative reactivity was found in 29/50 (58%) cases, weak in nine cases (18%), moderate in seven (14%) cases, and strong in five (10%) cases [Figure 3], [Figure 4] and [Graph 1]. A significant P value was obtained between PTEN expression in EH and EC with P = 0.0184 [Table 1].
Figure 1: (a) A case of endometrial hyperplasia shows rounded glands, some of these glands show slight angulations (H and E, ×200). (b) Strong positivity for phosphatase and tensin homolog in both epithelial glands and stroma (DAB, ×200). (c) Negative reactivity for p27 in contrast to its strong positivity for phosphatase and tensin homolog (DAB, ×200)

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Figure 2:(a) Another case of endometrial hyperplasia shows complex angulated glands with strong reactivity for phosphatase and tensin homolog (DAB, ×200). (b) Weak and patchy reactivity of gland and stroma for p27 (DAB, ×200)

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Figure 3: A case of endometrial carcinoma. (a) Negative staining for p27 (DAB, 400). (b) Strong staining for phosphate and tensin homolog (DAB,400)

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Figure 4: A case of endometrial carcinoma. (a) Weak focal staining for phosphate and tensin homolog (DAB, 100). (b) Strong staining for p27 (DAB,100)

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Table 1: Phosphatase and tensin homolog expression in both endometrial hyperplasia and endometrial carcinoma

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Regarding p27 expression in EH, loss of expression was found in 17/20 (85%) cases and weak in three (15%) cases, and no moderate or strong expression was found [Figure 1] and [Figure 2]. Concerning EC, loss of p27 expression or negative reactivity was found in 25/50 (50%) cases of EC, weak in 16 (32%) cases, moderate in six cases (12%), and strong in three cases (6%) [Figure 3] and [Figure 4]. A significant P value was obtained between p27 expression in EH and EC (P = 0.00334) [Table 1].

In EH, a significant P value was obtained between expressions of PTEN with that of p27 with P = 0.00019, while in EC, no significant P value was obtained between expressions of PTEN with that of p27 with P = 0.4591.

In EC cases, the cases were divided into Grade I (n = 30, 60%), II (n = 16, 32%), and III (n = 4, 8%). The differential reactivity of each FIGO grade is summarized in [Table 2]. Using one-way ANOVA for comparison between the results of the reactivity among three FIGO grading groups, no significant differences were obtained among all groups either for PTEN or p27 with P = 0.0534 and 0.9126, respectively [Table 2].
Table 2: Distribution of phosphatase and tensin homolog and p27 expressions according to the International Federation of Gynecology and Obstetrics grading system in the 50 studied endometrial carcinoma cases

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On the comparison between reactivity of PTEN in Grade I, II, and III with their counterparts in p27, using independent t-test, no significant difference was obtained between the three groups with P = 0.2907, 0.4269, and 0.0640 for FIGO I, II, and III, respectively [Graph 2] and [Table 3].

Table 3: Comparison between phosphatase and tensin homolog and p27 expressions according to the International Federation of Gynecology and Obstetrics grading system in the 50 studied endometrial carcinoma cases

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The result of analysis of reactivity of EH and EC cases for both antibodies are categorized into four major categories; PTEN+/p27+ (n = 2, 14; 10%, 28%), PTEN+/p27− (n = 5, 7; 25%, 14%), PTEN−/p27+ (n = 1, 11; 5%, 22%), and PTEN−/p27− (n = 12, 18; 60%, 36%) cases of EH and EC, respectively. There is no significant P value among these four categories using either Chi-square test, P = 0.06122, or the independent t- test for the subcategory, P = 0.0808.

Further analyses of the four categories into subcategories to illustrate the degree of reactivity are summarized in [Table 4].
Table 4: Distribution of anti-phosphatase and tensin homolog and p27 expressions in the endometrial hyperplasia and endometrial carcinoma cases

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  Discussion Top


The majority of the genetic defect in EC comes from PTEN gene inactivation through inactivation of the two alleles by large mutation and deletion. The tumor suppressor p27 is one of the Cip/Kip family members of CKIs, which plays a key role in the development of EC through negative regulation of the cell cycle progression; the normal regulation of p27 is being lost during progression of EC and undetectable or absent in some cases of EH.[38] Alternatively, the expression of p27 has been retained for a number of EC cases with cytoplasm mislocalization.[30] Consequently, both PTEN and p27 tumor suppressor genes alterations comprise an important group for developing EC.

In the present study, loss of PTEN expression was found in 7/20 (35%) and 29/50 (58%) cases of EH and EC, weak in 6/20 (30%) and 9/50 (18%), moderate in 4/20 (20%) and 7/50 (14%), and strong in 3 (15%) and 5 (10%) cases of EH and EC, respectively. A significant P value was obtained between PTEN expression in EH and EC (P = 0.01824).

These results are in agreement with the study of Mutter et al.,[39] who studied the PTEN expression in 33 EC cases and found a complete absence of PTEN expression in 20/33, 61% of EC cases. An et al.[38] studied the PTEN expression in EH and EC. They found that 4/13, 30% of EH and 40/61, 66% of cases of EC demonstrated a complete loss of PTEN expression. Orbo et al.[34] and Salvesen et al.[40] reported loss of PTEN protein expressions in 55% and 54% of EC cases, respectively. Allison et al.[41] showed that the PTEN expression in combination with particular histological features was of great importance to make a clear difference between EH and EC. Sarmadi et al.[35] detected loss of PTEN expression in 25% of EH and 52% of EC. In contrast to the above studies, the results of EH are somewhat far from the study of Kapucuoglu et al.,[36] who found a complete loss of PTEN in 20% of EH cases.

In the present study, a strong expression of PTEN was found in 5/50, 10% of EC cases which was distributed as follows: 2/19, 10.5% of cases of FIGO I; 1/10, 10% of cases in FIGO II; and 2/4, 50% of cases of FIGO III. Although the high percentage of the strong reactivity is seen in high FIGO grade (50%), there is no significant difference obtained between the histological grade and the degree of reactivity with P = 0.0534.

This may be attributed to the small number of cases, especially in FIGO III, which is considered as the major limitation of the current study. This finding was in agreement with An et al.,[38] who found no significant correlation with the histologic grade. Furthermore, it is in concordance with the study of Kimura et al.,[42] who studied PTEN expression in 117 EC cases and 20 cases of EH and found that PTEN staining scores of EC were increasing from FIGO Grade I–III, suggesting that the disturbed PTEN expression occurs in an early phase of tumorigenesis of well-differentiated EC and concluded that PTEN expression was decreased in well-differentiated EC associated with high levels of estrogen and progesterone receptors. On the other hand, the finding is in contrast to Salvesen et al.'s study[40] which revealed significant correlations with young age, low FIGO grading, and endometrioid subtype. Lacey et al.[43] compared the endometrial PTEN expression from patients with EH who developed to EC versus patients with EH who did not develop. They found that loss of PTEN expression was not linked with the progression to EC.

In the present study, PTEN expression was detected in seven cases of EH, three of seven cases of were diagnosed as atypical EH, and this finding was in agreement with the study of Lax,[44] which stated that in atypical EH, alterations of PTEN were present in approximately 50% of the cases.

In the current study, loss of p27 expression was found in 17/20 (85%) and 25/50 (50%) cases of EH and EC, weak in 3/20 (15%) and 16/50 (32%), moderate in 0/20 (0%) and 6/50 (12%), and strong in 0 (0%) and 3 (6%) cases of EH and EC, respectively. A significant P value was obtained between p27 expression in EH and EC (P = 0.00304).

These findings are in proximity to the study of Nycum et al.[45] and Lahav-Baratz et al.[46] Nycum et al.[45] studied the p27 expression in different stages of EC and found that expression of p27 was decreased in endometrial cancers compared with normal endometrial cells; furthermore, they found a p27-positive stain (>50% of cells) in 32.1%, 23.1%, 35.7%, and 36.4% for Stage 1–4, respectively, with no significant correlation among the grades; further, no association of p27 staining with age or histology was found. Alternatively, a trend in increasing staining with an increase in grade was found. Lahav-Baratz et al.[46] found that the p27 expression was seen in 41% of EC and found that there is no difference in expression with that seen in the proliferative phase of the endometrium.

Alternatively, these findings are in midline between the two extremities' groups of the studies; one showing high level of p27 above 80%[29],[38],[47],[48],[49] and one showing successive reductions in the p27 expression in a range from normal to endometrial carcinoma.[50],[51],[52],[53],[54],[55] These variable observations may be attributed to many factors as the number of specimens, different histologic types, and grades or the likelihood that the p27 has a complex role in the process of cell cycle regulation, which may clarify the incoherent observations.[54]

Bamberger et al.[52] analyzed 41 EC stained with p27 and found the negativity in 56.0% – low (29.3%), moderate (14.7%), and high (0.0%). Further, they revealed that all the p27-positive tumors were of grade G1. Schmitz et al.[53] studied the p27 expression in uterine serous papillary carcinoma and pointed to the presence of p27 expression alteration in 63% of cases displaying reduced p27 expression, suggesting that p27 abnormalities play an important role in the development of this disease. An et al.[38] found that decreased reactivity of p27 was found in 48/61 (79%) of 61 EC cases. In addition, they found no significant relationship between the degree of p27reactivity with the histological grade. Watanabe et al.[47] proved the positivity of p27 staining in the nuclei of 124/127, 97.6% EC cases; however, they found a correlation with the higher grade. Masciullo et al.[30] revealed a significant loss of p27 expression from proliferative endometrium (33%) through EH (50%) to EC (71%; P ≤ 0.001). Furthermore, they noted cytoplasmic localization of p27 193; 91% of 217 cases examined.

Horrée et al.[29] revealed that p27 expression was found in 67% of the tumor cells and conclude that, in EC carcinoma, p27 re-expression by hypoxia is HIF-1 alpha-dependent and leads to cell cycle arrest. Seeber et al.[48] found that expression of p27 was found in 86/93 (93%) of EC with no correlation between percentage p27-positive cells and grade. Gezginc et al.[54] reported that p27 reactivity decreased progressively as lesions progress from proliferative benign endometrium to frank carcinoma. Felix et al.[49] studied 281 EC and clarified the positivity in 80% of EC cases. In addition, the results are in somewhat close to the results of Al-Maghrabi et al.,[55] which revealed that p27 reactivity was 26.7% in carcinomas compared with 43% of the noncancerous endometrium.

In the present study, no significant difference was obtained between the p27 expression with the histological grade (P = 0.9126). This coincides with Ahn et al.[51] and Bamberger et al.,[52] who confirmed the correlation of decreased p27 expression with the higher grade and inconsistent with the study of Watanabe et al.,[47] who stated that the high expression of p27 in endometrial EC was correlated with a higher grade. This alteration in p27 expression may be attributed to the disorder of p27 degradation mechanism.[50]

In the present study, analysis of 11 cases expressing positivity for both antibodies revealed that 6/11 cases were of FIGO I Grade; among these cases, the strongest PTEN expression was found in three cases (one case in FIGO I, two cases for FIGO II); alternatively, two cases showed strong expression for p27 and distributed as one case for FIGO I and FIGO II. This denotes that the positive cases are mainly confined with the low and intermediate grading with weak expression among high grade. This observation coincides with An et al.,[38] who found that decreased p27 expression was found in 48 cases (79%) of 61 EC, and 76% (36 cases) of these cases also revealed decrease or even loss of PTEN reactivity.

On the other hand, positive expression of p27 associated with weak or loss of PTEN expression is found in 12 cases (one case showed weak PTEN expression) of EC; this means that the development of EC is independent on PTEN mutation alone, and there is an alternative pathway involved in upregulation of p27 independent on PTEN. This hypothesis is supported by findings of Akiyama-Abe et al.,[37] who found that not all EC showed bimodal loss of expression for PTEN and p27 and revealed that loss of PTEN expression was found in 56 cases (25%), while 165 (75% of cases) showed PTEN expression and nuclear p27 expression was found in 78 (35%) cases and lost in 143 (65%).

An et al.[38] found that 36/48 (76%) cases of positive PTEN revealed decrease or even loss of p27 reactivity. Furthermore, they found that four of five uterine serous carcinomas revealed strong p27 expression, which in turn showed intense PTEN expression. Also, they found a positive correlation between PTEN and p27 expression was statistically significant which in turn coincides with the results of the current study. Erkanli et al.[56] found that PTEN and p27 expressions were decreased in hyperplasia and carcinoma cases with significant differences obtained. In addition, a positive correlation was found between PTEN expression and p27. Neither PTEN nor p27 showed correlations with the grade although a higher mean survival in PTEN-positive cases was noticed.

The limitation of the current study is attributed to the small number of FIGO III cases. This may be due to health education and adventure of imaging techniques which aided to a large extent in the early detection. This view is supported by the limited number of cases towards the moderate and high grade. On the other hand, the main aim of the study is to find the extent of association of the PTEN with p27 in EC cases and not to find primarily the association of both separately with the histological grade.


  Conclusion Top


Not all cases of PTEN negative EC showing a p27 loss and vice versa. In addition, much debate about PTEN and p27 expression in EC is strongly present regarding the accurate percentage of their expressions and correlations with the histological grade more studies must be done to correlate between the degree of PTEN loss and p27 comprising all subtypes and grading of EC especially those of high FIGO grade.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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