© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 4, 309-314,
February 21, 2001
© 2001 Oxford University Press
REPORT |
Levels of Hypoxia-Inducible Factor-1
During Breast Carcinogenesis
Affiliations of authors: R. Bos, E. C. M. Mommers, P. J. van Diest (Department of Pathology), H. M. Pinedo, E. van der Wall (Department of Medical Oncology), Free University Hospital, Amsterdam, The Netherlands; H. Zhong, J. W. Simons, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA; C. F. Hanrahan (Brady Urological Institute), G. L. Semenza (Departments of Pediatrics and Medicine, Institute of Genetic Medicine), M. D. Abeloff (Oncology Center), The Johns Hopkins University School of Medicine, Baltimore, MD.
Correspondence to: Elsken van der Wall, M.D., Ph.D., Department of Medical Oncology, Free University Hospital, P.O. Box 7057, NL-1007 MB Amsterdam, The Netherlands (e-mail: e.vanderwall{at}azvu.nl).
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ABSTRACT |
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Background: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases. In this report, we investigated whether the level of HIF-1
is increased during carcinogenesis in breast tissue and is associated with other tumor biomarkers. Methods: Paraffin-embedded clinical specimens from five pathologic stages of breast tumorigenesis and from normal breast tissue were used. HIF-1 protein and the biomarkers vascular endothelial growth factor (VEGF), HER-2/neu, p53, Ki-67, and estrogen receptor (ER) were identified immunohistochemically, and microvessel density (a measure of angiogenesis) was determined. Associations among levels of HIF-1 and these biomarkers were tested statistically. All statistical tests are two-sided. Results: The frequency of HIF-1-positive cells in a specimen increased with the specimen's pathologic stage (P<.001, 
2 test for trend) as follows: normal breast tissue (0 specimens with 
1% HIF-1-positive cells in 10 specimens tested), ductal hyperplastic lesions (0 in 10), well-differentiated ductal carcinomas in situ (DCIS) (11 in 20), well-differentiated invasive breast cancers (12 in 20), poorly differentiated DCIS (17 in 20), and poorly differentiated invasive carcinomas (20 in 20). Increased levels of HIF-1 were statistically significantly associated with high proliferation and increased expression of VEGF and ER proteins. In DCIS lesions, increased levels of HIF-1 were statistically significantly associated with increased microvessel density. HIF-1 showed a borderline association with HER-2/neu but no association with p53. Conclusions: The level of HIF-1 increases as the pathologic stage increases and is higher in poorly differentiated lesions than in the corresponding type of well-differentiated lesions. Increased levels of HIF-1 are associated with increased proliferation and increased expression of ER and VEGF. Thus, increased levels of HIF-1 are potentially associated with more aggressive tumors.
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INTRODUCTION |
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The role of hypoxia-inducible factor-1
(HIF-1) is under increasing scrutiny by cancer researchers (1). HIF-1 binds the consensus sequence 5'-RCGTG-3' (where R is any purine) in the hypoxia-response elements of various target genes (2). HIF-1 activates the transcription of many genes controlling glucose transporters, glycolytic enzymes, gluconeogenesis, high-energy phosphate metabolism, growth factors, erythropoiesis, heme metabolism, iron transport, vasomotor regulation, and nitric oxide synthesis (2,3) and, thus, may increase the survival of tumor cells under hypoxic conditions. Hypoxia influences the proliferation of tumor cells (4), the rate of apoptotic cell death (5), and metastasis (6). In addition, by activating transcription of the vascular endothelial growth factor (VEGF) gene, HIF-1 is considered to be a central initiator of angiogenic activity in tumors (7–10).
The level of HIF-1 in cells is dependent on the intracellular oxygen concentration (11,12). When cells have normal concentrations of oxygen, HIF-1 protein is continuously degraded via the ubiquitin pathway. However, under low concentrations of oxygen (hypoxic conditions), the ubiquitination of HIF-1 is blocked, the protein is stabilized (11,13), and thus the protein's intracellular levels increase. Although the exact mechanism of oxygen sensing remains to be elucidated, the cell probably senses its oxygen concentration through reactive oxygen species, so that stabilization of the HIF-1 protein is said to be redox induced (14).
A nuclear localization signal at the C-terminal end of HIF-1 allows its transport from the cytoplasm to the nucleus, where it forms an active HIF-1 complex by binding to HIF-1
. HIF-1 can form heterodimers with other proteins, such as the aryl hydrocarbon receptor (15), and is constitutively and abundantly present (11,16). Thus, the amount of HIF-1 protein in the nucleus is rate limiting and determines the functional activity of the HIF-1 complex (2).
The level of the HIF-1 protein is inversely related to the oxygen tension in cultured cells (12) and in vivo (11). Hypoxic oxygen tensions that induce HIF-1 levels have been demonstrated in tumors in vivo and are associated with a poor clinical outcome (6,17,18). HIF-1 activity also is associated with tumor progression and angiogenesis in xenograft assays (19–21). These observations and the fact that increased levels of HIF-1 are found in many common human cancers at diagnosis (1,2) suggest that HIF-1 has an important role in cancer progression (22).
Since the discovery of HIF-1 (23), the characteristics of HIF-1 have been explored in many studies using cultured cell lines. In this study, we focused on the role of HIF-1 in human breast carcinogenesis. Because angiogenesis is necessary for hyperplastic epithelial cells to progress to malignant cells (24) and because HIF-1 may induce angiogenesis by activating transcription of the VEGF gene, we propose that HIF-1 plays a role in breast carcinogenesis. This hypothesis is supported by previous findings that VEGF, one of the most potent molecules in angiogenesis, is increased in ductal carcinoma in situ (DCIS) (25). We tested this hypothesis by evaluating the levels of HIF-1 in normal breast tissue and in different stages of breast cancer development (usual ductal hyperplasia, DCIS, and invasive breast cancer) and by determining whether the level of HIF-1 was associated with proliferation (Ki-67), microvessel formation, and/or the expression of VEGF, HER-2/neu, p53, and the estrogen receptor (ER).
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MATERIALS AND METHODS |
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The level of HIF-1 was examined in randomly selected samples of breast tissue from patients. These samples had been deposited in the breast cancer tumor banks of the pathology departments of the Free University Hospital, Amsterdam, The Netherlands, and the Gooi-Noord Hospital, Blaricum, The Netherlands. Normal breast tissue was from reduction mammoplasties performed on patients without proliferative breast disease. Specimens of pure ductal hyperplasia, pure DCIS, and invasive carcinoma were obtained from excision biopsy procedures or mastectomies. None of the patients with invasive breast cancer had received any preoperative therapy. All specimens were fixed in neutral 4% buffered formaldehyde. Informed consent to anonymously use leftover patient material for scientific purposes was a standard item in the treatment contract with the patients.
We examined normal breast tissue (from 10 patients), usual ductal hyperplasia (from 10 patients), well-differentiated DCIS (from 20 patients), poorly differentiated DCIS (from 20 patients), invasive carcinoma grade 1 (from 20 patients), and invasive carcinoma grade 3 (from 20 patients). Grading of DCIS and of invasive cancer was done according to the procedure of Holland et al. (26) and Elston and Ellis (27), respectively. The grading pathologist (P. J. van Diest) was blinded in scoring all specimens for HIF-1 with respect to other biomarkers.
Immunohistochemistry
Table 1
presents all antibodies, dilutions, incubation times, and antigen-retrieval methods used. Immunohistochemistry was performed on 4-µm-thick slides. After deparaffinization and rehydration, endogenous peroxidase activity was blocked for 30 minutes in methanol containing 0.3% hydrogen peroxide. After antigen retrieval, a cooling-off period of 20 minutes preceded the incubation of the primary antibody. Thereafter, the catalyzed signal amplification system (DAKO, Glostrup, Denmark) was used for HIF-1 staining according to the manufacturer's instructions. All other antibodies were detected by a standard avidin–biotin complex method with a biotinylated rabbit anti-mouse antibody (DAKO) and an avidin–biotin complex (DAKO). All stainings were developed with diaminobenzidine. Before the slides were mounted, all sections were counterstained for 45 seconds with hematoxylin and dehydrated in alcohol and xylene. Appropriate negative controls (obtained by omission of the primary antibody) and positive controls were used throughout; for HIF-1-negative and -positive controls, respectively, we used normoxic and hypoxic prostate cancer TSU cells, which were embedded in paraffin and provided by Dr. A. M. DeMarzo (The Johns Hopkins University School of Medicine, Baltimore, MD).
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Quantification
For HIF-1 staining, only cells with completely and darkly stained epithelial nuclei were regarded as positive, and this nuclear staining was interpreted as an increased level; cytoplasmic staining, observed occasionally, was ignored because active HIF-1 is located only in the nucleus. The fraction of nuclei with an increased level of HIF-1 or p53 or Ki-67 positivity was estimated visually by two observers (R. Bos and P. J. van Diest). In DCIS specimens, the angiogenic activity was assessed by scoring the presence of a vascular rim around the ducts and by estimating the microvessel density in the surrounding stroma as described previously by Guidi et al. (28). In invasive cancers, microvessels were manually counted by use of an ocular grid at a magnification of x400, following the criteria of Weidner et al. (29,30) as described previously (31). In short, in four adjacent fields of vision in the most vascularized area ("hot spot," total area = 0.6 mm2), microvessels were counted and expressed as the microvessel density per millimeters square.
HER-2/neu staining was scored as negative or positive (membrane staining). VEGF expression was scored as weakly or strongly positive. ER status was determined by the evaluation of the histoscore as described previously (32); a histoscore of 100 or more was regarded as positive.
Statistical Methods
To evaluate whether the frequency of cells with the elevated levels of HIF-1 increased during breast carcinogenesis, we performed a 2 test for trend, grouping the results as normal, hyperplasia, DCIS, or invasive cancer. Associations between increased levels of HIF-1 and the other biomarkers were analyzed with Fisher's exact test. The mean percentages of HIF-1-positive cells in the different histologic groups were compared with the Mann–Whitney test. All analyses were performed with the SPSS package of computer programs for Windows, version 9.0.1, 1999 (SPSS Inc., Chicago, IL). P values of less than .05 were regarded as statistically significant. All statistical tests are two-sided.
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RESULTS |
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A summary of the HIF-1
nuclear staining in normal breast tissue and tissues from five stages of breast carcinogenesis is provided in Table 2. Normal breast tissue (n = 10) and hyperplastic lesions (n = 10) showed no detectable HIF-1. In contrast, increased levels of HIF-1 were found in well-differentiated DCIS specimens (11 specimens had 1% immunopositive cells of 20 specimens tested), with the number of positive specimens further increasing in well-differentiated invasive breast (12 of 20). This trend continued with poorly differentiated DCIS lesions (17 of 20) and poorly differentiated invasive carcinomas (20 of 20). In 28 of 30 HIF-1-positive specimens that contained necrosis, regional HIF-1 positivity was especially noted around the areas of necrosis (Fig. 1, D). Occasionally, a few cells with increased HIF-1 levels were observed in ductal hyperplastic areas adjacent to invasive cancer and in areas of atypical ductal hyperplasia.
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Statistical analysis (
2 test) of the HIF-1 data showed a statistically significant increase in the number of cells with increased levels of HIF-1 over the progression spectrum (normal = 0 of 10; hyperplasia = 0 of 10; DCIS = 28 of 40; invasive cancer = 32 of 40; P<.001).
More poorly differentiated (DCIS and invasive cancer) lesions (37 of 40) than the corresponding well-differentiated lesions (23 of 40) showed increased levels of HIF-1 (P<.001). Well-differentiated and poorly differentiated DCIS lesions had statistically different levels of HIF-1 (P = .028), as did well-differentiated and poorly differentiated invasive breast cancers (P<.001). Also, the percentage of cells with increased levels of HIF-1 varied with different pathology, with a statistically significant higher (P<.001) percentage of positive cells in poorly differentiated specimens (Table 2
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Table 3 shows comparisons of increased levels of HIF-1 with various biomarkers. Even in this small dataset, VEGF expression (P = .001), Ki-67 expression (P<.001) (10% threshold), and ER status (P = .001) were highly positively associated with increased levels of HIF-1. HER-2/neu showed a positive, but borderline, association (P = .053) with HIF-1. However, p53 expression (5% threshold for positivity) was not associated with increased levels of HIF-1. In the invasive cancers, a nearly positive association was found between HIF-1 and microvessel density (P<.120). Stromal vascular density in DCIS showed a statistically significant positive association with HIF-1 (P = .041), but vascular rim formation did not (P = 1.00).
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HIF-1
positivity was found in 29 of 34 specimens containing necrosis compared with 31 of 46 specimens without necrosis. The mean percentage of HIF-1-positive cells was higher in specimens with necrosis (P = .019), a trend also visible in the subgroups of DCIS (P = .08) and invasive lesions (P = .02). |
DISCUSSION |
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The purpose of this study was to determine whether increased levels of HIF-1
could be detected during different stages of carcinogenesis in human breast tissue. HIF-1 appears to be involved in angiogenesis during prostate carcinogenesis (33), and recent data (34) show that increased levels of HIF-1 represent an unfavorable characteristic in early cervical cancer. In this study, we did not detect increased levels of HIF-1 in specimens from normal breast and areas with ductal hyperplasia, but we did detect increased levels in the majority of DCIS and invasive cancer specimens. Levels of HIF-1 increased as the degree of malignancy increased, confirming earlier pilot data (1) suggesting that HIF-1 may be a biomarker of preinvasive human breast cancers. In addition, we observed that an increased level of HIF-1 was associated with high proliferation, strong VEGF expression, and ER positivity as well as with angiogenesis but only in the subgroup of DCIS lesions. To our knowledge, this is the first report to implicate increased levels of HIF-1 in early human breast carcinogenesis.
A statistically significant association was observed between increased levels of HIF-1 and VEGF expression. Furthermore, a positive association was observed between increased levels of HIF-1 and intratumoral microvessel density in DCIS, supporting a role for HIF-1 in angiogenesis during breast carcinogenesis. Our findings are consistent with a previous report (4) in xenografts of animal tumors and transgenic models, which showed HIF-1 involvement in the angiogenic phenotype of cancer.
It is interesting that increased levels of HIF-1 were most pronounced in poorly differentiated lesions, which supports the previously proposed progression model for breast cancer (35,36). In this model, well-differentiated cancers arise from well-differentiated precursor lesions and poorly differentiated cancers from poorly differentiated precursor lesions. Poorly differentiated lesions (in the preinvasive and invasive states) are clinically more aggressive. The observed increased levels of HIF-1 in poorly differentiated DCIS may indicate a higher likelihood that this lesion will acquire invasive properties and that the resulting poorly differentiated invasive lesions will have a poorer prognosis.
The association between increased levels of HIF-1 and ER status at first seemed surprising but was consistent with the following data: HIF-1 is known to stimulate the production of VEGF (7), and the VEGF gene has functional ER response elements (37). Furthermore, estrogen stimulation increases phosphatidylinositol 3-hydroxykinase activity (38), which belongs to a signaling pathway that may play a role in HIF-1 activation (33). The relationship of estrogen action, ER interactions, and HIF-1-driven genes in breast cancer certainly merits further investigation.
Several mechanisms, which are not mutually exclusive, that induce elevated levels of HIF-1 may be active in breast carcinogenesis. First, neoplastic breast lesions may be hypoxic so that HIF-1 is induced by low oxygen tension, as demonstrated in cultured cells (39), animal models (16), and hypoxic myocardium (40). Such hypoxic conditions occur in solid cancers, but it is not yet known whether this holds true in DCIS (microhypoxia). It is interesting to note, however, the presence of HIF-1-positive cells around areas of necrosis. Cells with increased levels of HIF-1 were also found regularly around areas of necrosis in invasive cancers. In poorly differentiated DCIS and invasive lesions, necrosis occurred more frequently. The difference in levels of HIF-1 protein between well-differentiated and poorly differentiated lesions may, therefore, also be hypoxia related. Studies addressing the intratumoral oxygen level in human breast cancer are required to define this important epigenetic parameter, which may have functional effects on HIF-1-activated genes.
Second, activated oncogenes and loss-of-function mutations in tumor suppressor genes, such as PTEN (phosphatase and tensin homolog deleted on chromosome 10), VHL (von Hippel–Lindau tumor suppressor gene), and p53, have been shown to modulate HIF-1 levels in certain tumor types (2). For example, loss of p53 function has been shown in vitro to augment HIF-1 and VEGF expression (21) and, under hypoxic conditions, HIF-1 is phosphorylated by extracellularly regulated kinases (41,42), confirming the potential role of the PI(3)K and mitogen-activated protein kinase pathways and upstream oncogenes. HER-2/neu activates both pathways, and mutations in this gene are among the most common genomic alteration in DCIS and early breast cancer. In our study, HIF-1 levels and HER-2/neu status were indeed positively associated. Increased levels of HIF-1 can also occur as an effect of growth factor activation of the PI(3)K/AKT (protein kinase B)/FRAP (FK506 binding protein [FKBP])-rapamycin-associated protein pathway (33,43), as has been shown in tumor types other than breast cancer.
Third, activated immune responses during inflammation by the proinflammatory cytokines interleukin 1 and tumor necrosis factor- (44) may also modulate HIF-1 activity in tumors. Both cytokines are important in the growth and differentiation of human breast cancer (45,46).
Finally, this study suggests breast cancer angiogenesis may be driven in part by HIF-1. We detected a statistically significant positive association between increased levels of HIF-1 protein and VEGF expression in human breast tissue. HIF-1 activates angiogenesis by stimulating VEGF transcription (7), and VEGF is induced by both oncogenic transformation and hypoxia (21,47,48). Increased expression of VEGF and its receptors Flt-1 and Flk-1 have been demonstrated in breast cancer (49,50). Increased VEGF expression in primary breast cancer confers a poorer prognosis at clinical presentation. Increased angiogenesis has also been reported in DCIS (29). In our study, increased levels of HIF-1 were positively associated with both VEGF and microvessel density. These data support an angiogenesis-inducing role for HIF-1 during breast carcinogenesis. HIF-1 immunostaining may serve as a surrogate biomarker of angiogenic potential of breast cancer and deserves further large-scale clinical investigations.
It was interesting to note occasional nuclei with increased levels of HIF-1 in usual ductal hyperplasia next to invasive cancers and areas of atypical ductal hyperplasia. Usual ductal hyperplasia (and even normal lobules) next to invasive cancer has been shown to harbor morphologic (51) and genetic (52) changes and, thus, should be considered to be a more advanced lesion than pure ductal hyperplasia. Atypical ductal hyperplasia should be placed between usual ductal hyperplasia and well-differentiated DCIS in the breast progression spectrum (36) and so may be the earliest pure preinvasive breast lesion with increased levels of HIF-1.
Increased levels of HIF-1 protein were observed at the earliest pathologically detectable stages of breast cancer carcinogenesis and were increased in dedifferentiated malignant tissue. Thus, we urge that therapeutics specifically targeting and inhibiting HIF-1 (33,53,54) be rationally tested to prevent malignant progression in early breast cancer.
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NOTES |
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Supported by the AEGON International Scholarship in Oncology (Public Health Service [PHS] grant CA58236 [to R. Bos] from the National Cancer Institute [NCI], National Institutes of Health, Department of Health and Human Services); by the Avon Breast Cancer Crusade (H. Zhong, J. W. Simons); by grant DAMD 17–98-1–8475 from the U.S. Department of Defense; by the CaPCure Foundation; and by PHS grant CA58236 from the NCI.
We thank Dr. A. M. DeMarzo (Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD) for providing the embedded HIF-1 TSU-expressing cell line, Dr. H.V. Stel (a pathologist at the Gooi-Noord Hospital, Blaricum, The Netherlands) for some tumor material, Mrs. P. van der Groep for technical assistance with the immunostaining, and Mrs. K. Heaney for assistance in preparing the manuscript for submission.
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M. Schindl, S. F. Schoppmann, H. Samonigg, H. Hausmaninger, W. Kwasny, M. Gnant, R. Jakesz, E. Kubista, P. Birner, and G. Oberhuber Overexpression of Hypoxia-inducible Factor 1{alpha} Is Associated with an Unfavorable Prognosis in Lymph Node-positive Breast Cancer Clin. Cancer Res., June 1, 2002; 8(6): 1831 - 1837. [Abstract] [Full Text] [PDF]
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A. Jogi, I. Ora, H. Nilsson, A. Lindeheim, Y. Makino, L. Poellinger, H. Axelson, and S. Pahlman Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype PNAS, May 14, 2002; 99(10): 7021 - 7026. [Abstract] [Full Text] [PDF]
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C. Pellizzaro, D. Coradini, and M. G. Daidone Modulation of angiogenesis-related proteins synthesis by sodium butyrate in colon cancer cell line HT29 Carcinogenesis, May 1, 2002; 23(5): 735 - 740. [Abstract] [Full Text] [PDF]
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G. Hopfl, R. H. Wenger, U. Ziegler, T. Stallmach, O. Gardelle, R. Achermann, M. Wergin, B. Kaser-Hotz, H. M. Saunders, K. J. Williams, et al. Rescue of Hypoxia-inducible Factor-1{alpha}-deficient Tumor Growth by Wild-Type Cells Is Independent of Vascular Endothelial Growth Factor Cancer Res., May 1, 2002; 62(10): 2962 - 2970. [Abstract] [Full Text] [PDF]
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 K. Ozaki, J. K. Haseman, J. R. Hailey, R. R. Maronpot, and A. Nyska Association of Adrenal Pheochromocytoma and Lung Pathology in Inhalation Studies with Particulate Compounds in the Male F344 Rat--The National Toxicology Program Experience Toxicol Pathol, February 1, 2002; 30(2): 263 - 270. [Abstract] [PDF]
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R. Bos, J. J.M. van der Hoeven, E. van der Wall, P. van der Groep, P. J. van Diest, E. F.I. Comans, U. Joshi, G. L. Semenza, O. S. Hoekstra, A. A. Lammertsma, et al. Biologic Correlates of 18Fluorodeoxyglucose Uptake in Human Breast Cancer Measured by Positron Emission Tomography J. Clin. Oncol., January 15, 2002; 20(2): 379 - 387. [Abstract] [Full Text] [PDF]
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R. Bos, P. J. van Diest, and E. van der Wall RESPONSE: Re: Levels of Hypoxia-Inducible Factor-1{alpha} During Breast Carcinogenesis J Natl Cancer Inst, August 1, 2001; 93(15): 1177 - 1177. [Full Text] [PDF]
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