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Special Issue "Cellular and Molecular Mechanisms of Bone Metastasis"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2016).

Special Issue Editor

Prof. Dr. Maria Alfonsina Desiderio
E-Mail Website
Guest Editor
Department of Biomedical Sciences for Health, Molecular Pathology Laboratory, University of Milan, Milano, Italy
Interests: bone metastasis from breast carcinoma; hepatocyte growth factor; Met receptor; hypoxia; microenvironment; epithelial-mesenchymal transition; transcriptional regulation
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Metastasis to the skeleton is the principal cause of death of patients with breast and prostate cancer, and multiple myeloma. The molecular pathogenesis of bone metastasis represents one of the leading aspects considered by the Molecular Medicine, because of the importance of deepening the biology of the process and for personalized therapy. The multidisciplinary approach of study is strongly desirable due to the multiple facets of the bone metastasis process, which are supported by genetic and epigenetic mechanisms, through systemic signals and local physical and biological stimuli. The bone metastatic process may be investigated from different points of view, including the pathology of cellular events, nanotechnology and structural/biological engineering, as well as the molecular biology of invasiveness, of mesenchymal-epithelial transition and its reversion, and of transcription factor regulation.

This Special Issue, “Cellular and Molecular Mechanisms of Bone Metastasis”, will cover a selection of recent research topics and current review articles in the field of invasiveness and bone metastasis.

Prof. Dr. Maria Alfonsina Desiderio
Guest Editor

Manuscript Submission Information

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Keywords

  • bone metastasis
  • breast carcinoma
  • prostate carcinoma
  • multiple myeloma
  • hypoxia
  • growth factors
  • epithelial-mesenchymal transition
  • epigenetic mechanisms
  • autophagy

Published Papers (12 papers)

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Research

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Article
The Effect of Everolimus in an In Vitro Model of Triple Negative Breast Cancer and Osteoclasts
Int. J. Mol. Sci. 2016, 17(11), 1827; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17111827 - 01 Nov 2016
Cited by 16 | Viewed by 2470
Abstract
Metastatic bone disease has a major impact on morbidity of breast cancer (BC) patients. Alterations in mTOR signaling are involved both in cancer progression and in osteoclast differentiation. The purpose of this study was to assess the role of mTOR inhibitor Everolimus (Eve) [...] Read more.
Metastatic bone disease has a major impact on morbidity of breast cancer (BC) patients. Alterations in mTOR signaling are involved both in cancer progression and in osteoclast differentiation. The purpose of this study was to assess the role of mTOR inhibitor Everolimus (Eve) on osteoclastogenesis induced by triple negative BC cells. To this aim, we developed an in vitro human model of osteoclastogenesis from peripheral blood monocytes co-cultured with the triple negative SCP2 and the hormonal receptor positive MCF7 cell lines. Osteoclastogenesis was evaluated by TRAP staining, evaluation of F actin rings and Calcitonin Receptor expression. Eve significantly reduced differentiation induced by cancer cells and resulted more effective when evaluated in combination with Denosumab and Zoledronic Acid (Zol). Combination with Zol showed a total abrogation of osteoclast differentiation induced by the triple negative cell line, not by MCF7. Finally, we observed that Eve was active in the inhibition of the crosstalk between cancer cells and osteoclasts reproduced by our model, highlighting a new therapeutic choice for the subsetting of triple negative BC patients. We observed a difference in the response to bone-targeted therapy with respect to BC subtypes. Our model may represent a valid platform for preclinical trials on bone-targeted drugs and for the study of the interplay of BC with bone stromal cells. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Article
Assessing Heterogeneity of Osteolytic Lesions in Multiple Myeloma by 1H HR-MAS NMR Metabolomics
Int. J. Mol. Sci. 2016, 17(11), 1814; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17111814 - 31 Oct 2016
Cited by 4 | Viewed by 2217
Abstract
Multiple myeloma (MM) is a malignancy of plasma cells characterized by multifocal osteolytic bone lesions. Macroscopic and genetic heterogeneity has been documented within MM lesions. Understanding the bases of such heterogeneity may unveil relevant features of MM pathobiology. To this aim, we deployed [...] Read more.
Multiple myeloma (MM) is a malignancy of plasma cells characterized by multifocal osteolytic bone lesions. Macroscopic and genetic heterogeneity has been documented within MM lesions. Understanding the bases of such heterogeneity may unveil relevant features of MM pathobiology. To this aim, we deployed unbiased 1H high-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) metabolomics to analyze multiple biopsy specimens of osteolytic lesions from one case of pathological fracture caused by MM. Multivariate analyses on normalized metabolite peak integrals allowed clusterization of samples in accordance with a posteriori histological findings. We investigated the relationship between morphological and NMR features by merging morphological data and metabolite profiling into a single correlation matrix. Data-merging addressed tissue heterogeneity, and greatly facilitated the mapping of lesions and nearby healthy tissues. Our proof-of-principle study reveals integrated metabolomics and histomorphology as a promising approach for the targeted study of osteolytic lesions. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Article
Development of a Patient-Derived Xenograft (PDX) of Breast Cancer Bone Metastasis in a Zebrafish Model
Int. J. Mol. Sci. 2016, 17(8), 1375; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17081375 - 22 Aug 2016
Cited by 47 | Viewed by 4509
Abstract
Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX) rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary [...] Read more.
Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX) rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary culture of bone metastasis derived from a 67-year-old patient with breast cancer was cultured and then injected into zebrafish (ZF) embryos to study its metastatic potential. In vivo behavior and results of gene expression analyses of the primary culture were compared with those of cancer cell lines with different metastatic potential (MCF7 and MDA-MB-231). The MCF7 cell line, which has the same hormonal receptor status as the bone metastasis primary culture, did not survive in the in vivo model. Conversely, MDA-MB-231 disseminated and colonized different parts of the ZF, including caudal hematopoietic tissues (CHT), revealing a migratory phenotype. Primary culture cells disseminated and in later stages extravasated from the vessels, engrafting into ZF tissues and reaching the CHT. Primary cell behavior reflected the clinical course of the patient’s medical history. Our results underline the potential for using PDX models in bone metastasis research and outline new methods for the clinical application of this in vivo model. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Article
Leptin Receptor Metabolism Disorder in Primary Chondrocytes from Adolescent Idiopathic Scoliosis Girls
Int. J. Mol. Sci. 2016, 17(7), 1160; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17071160 - 20 Jul 2016
Cited by 18 | Viewed by 2611
Abstract
To investigate the underlying mechanisms of low metabolic activity of primary chondrocytes obtained from girls with adolescent idiopathic scoliosis (AIS); AIS is a spine-deforming disease that often occurs in girls. AIS is associated with a lower bone mass than that of healthy individuals [...] Read more.
To investigate the underlying mechanisms of low metabolic activity of primary chondrocytes obtained from girls with adolescent idiopathic scoliosis (AIS); AIS is a spine-deforming disease that often occurs in girls. AIS is associated with a lower bone mass than that of healthy individuals and osteopenia. Leptin was shown to play an important role in bone growth. It can also regulate the function of chondrocytes. Changes in leptin and Ob-R levels in AIS patients have been reported in several studies. The underlying mechanisms between the dysfunction of peripheral leptin signaling and abnormal chondrocytes remain unclear; The following parameters were evaluated in AIS patients and the control groups: total serum leptin levels; Ob-R expression in the plasma membrane of primary chondrocytes; JAK2 and STAT3 phosphorylation status. Then, we inhibited the lysosome and proteasome and knocked down clathrin heavy chain (CHC) expression in primary chondrocytes isolated from girls with AIS and evaluated Ob-R expression. We investigated the effects of leptin combined with a lysosome inhibitor or CHC knockdown in primary chondrocytes obtained from AIS patients; Compared with the controls, AIS patients showed similar total serum leptin levels, reduced JAK2 and STAT3 phosphorylation, and decreased cartilage matrix synthesis in the facet joint. Lower metabolic activity and lower membrane expression of Ob-R were observed in primary chondrocytes from the AIS group than in the controls. Lysosome inhibition increased the total Ob-R content but had no effect on the membrane expression of Ob-R or leptin’s effects on AIS primary chondrocytes. CHC knockdown upregulated the membrane Ob-R levels and enhanced leptin’s effects on AIS primary chondrocytes; The underlying mechanism of chondrocytes that are hyposensitive to leptin in some girls with AIS is low plasma membrane Ob-R expression that results from an imbalance between the rate of receptor endocytosis and the insertion of newly synthesized receptors into the membrane. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Article
The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages
Int. J. Mol. Sci. 2016, 17(4), 443; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040443 - 25 Mar 2016
Cited by 7 | Viewed by 2512
Abstract
Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and [...] Read more.
Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Review

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Review
What Is Breast in the Bone?
Int. J. Mol. Sci. 2016, 17(10), 1764; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17101764 - 22 Oct 2016
Cited by 15 | Viewed by 3443
Abstract
The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is [...] Read more.
The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%–50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural “recycling” of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Review
Cancer Cell Colonisation in the Bone Microenvironment
Int. J. Mol. Sci. 2016, 17(10), 1674; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17101674 - 04 Oct 2016
Cited by 63 | Viewed by 3881
Abstract
Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow [...] Read more.
Bone metastases are a common complication of epithelial cancers, of which breast, prostate and lung carcinomas are the most common. The establishment of cancer cells to distant sites such as the bone microenvironment requires multiple steps. Tumour cells can acquire properties to allow epithelial-to-mesenchymal transition, extravasation and migration. Within the bone metastatic niche, disseminated tumour cells may enter a dormancy stage or proliferate to adapt and survive, interacting with bone cells such as hematopoietic stem cells, osteoblasts and osteoclasts. Cross-talk with the bone may alter tumour cell properties and, conversely, tumour cells may also acquire characteristics of the surrounding microenvironment, in a process known as osteomimicry. Alternatively, these cells may also express osteomimetic genes that allow cell survival or favour seeding to the bone marrow. The seeding of tumour cells in the bone disrupts bone-forming and bone-resorbing activities, which can lead to macrometastasis in bone. At present, bone macrometastases are incurable with only palliative treatment available. A better understanding of how these processes influence the early onset of bone metastasis may give insight into potential therapies. This review will focus on the early steps of bone colonisation, once disseminated tumour cells enter the bone marrow. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Review
Implications of Hypoxia in Breast Cancer Metastasis to Bone
Int. J. Mol. Sci. 2016, 17(10), 1669; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17101669 - 30 Sep 2016
Cited by 36 | Viewed by 4293
Abstract
Most solid tumors contain regions of hypoxia in which increased cell proliferation promotes increased oxygen consumption and the condition is further exacerbated as cancer cells become localized far from a functional blood vessel, further decreasing the oxygen supply. An important mechanism that promotes [...] Read more.
Most solid tumors contain regions of hypoxia in which increased cell proliferation promotes increased oxygen consumption and the condition is further exacerbated as cancer cells become localized far from a functional blood vessel, further decreasing the oxygen supply. An important mechanism that promotes cell adaptation to hypoxic conditions is the expression of hypoxia-inducible factors (HIFs). Hypoxia-inducible factors transcriptionally regulate many genes involved in the invasion and metastasis of breast cancer cells. Patients, whose primary tumor biopsies show high HIF expression levels, have a greater risk of metastasis. The current review will highlight the potential role of hypoxia in breast cancer metastasis to the bone by considering the regulation of many steps in the metastatic process that include invasion, migration, margination and extravasation, as well as homing signals and regulation of the bone microenvironment. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Review
Molecular Mechanisms of Bone Metastasis: Which Targets Came from the Bench to the Bedside?
Int. J. Mol. Sci. 2016, 17(9), 1415; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091415 - 27 Aug 2016
Cited by 25 | Viewed by 3712
Abstract
Bone metastases ultimately result from a complex interaction between cancer cells and bone microenvironment. However, prior to the colonization of the bone, cancer cells must succeed through a series of steps that will allow them to detach from the primary tumor, enter into [...] Read more.
Bone metastases ultimately result from a complex interaction between cancer cells and bone microenvironment. However, prior to the colonization of the bone, cancer cells must succeed through a series of steps that will allow them to detach from the primary tumor, enter into circulation, recognize and adhere to specific endothelium, and overcome dormancy. We now know that as important as the metastatic cascade, tumor cells prime the secondary organ microenvironment prior to their arrival, reflecting the existence of specific metastasis-initiating cells in the primary tumor and circulating osteotropic factors. The deep comprehension of the molecular mechanisms of bone metastases may allow the future development of specific anti-tumoral therapies, but so far the approved and effective therapies for bone metastatic disease are mostly based in bone-targeted agents, like bisphosphonates, denosumab and, for prostate cancer, radium-223. Bisphosphonates and denosumab have proven to be effective in blocking bone resorption and decreasing morbidity; furthermore, in the adjuvant setting, these agents can decrease bone relapse after breast cancer surgery in postmenopausal women. In this review, we will present and discuss some examples of applied knowledge from the bench to the bed side in the field of bone metastasis. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Review
In Vitro Co-Culture Models of Breast Cancer Metastatic Progression towards Bone
Int. J. Mol. Sci. 2016, 17(9), 1405; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091405 - 25 Aug 2016
Cited by 18 | Viewed by 6990
Abstract
Advanced breast cancer frequently metastasizes to bone through a multistep process involving the detachment of cells from the primary tumor, their intravasation into the bloodstream, adhesion to the endothelium and extravasation into the bone, culminating with the establishment of a vicious cycle causing [...] Read more.
Advanced breast cancer frequently metastasizes to bone through a multistep process involving the detachment of cells from the primary tumor, their intravasation into the bloodstream, adhesion to the endothelium and extravasation into the bone, culminating with the establishment of a vicious cycle causing extensive bone lysis. In recent years, the crosstalk between tumor cells and secondary organs microenvironment is gaining much attention, being indicated as a crucial aspect in all metastatic steps. To investigate the complex interrelation between the tumor and the microenvironment, both in vitro and in vivo models have been exploited. In vitro models have some advantages over in vivo, mainly the possibility to thoroughly dissect in controlled conditions and with only human cells the cellular and molecular mechanisms underlying the metastatic progression. In this article we will review the main results deriving from in vitro co-culture models, describing mechanisms activated in the crosstalk between breast cancer and bone cells which drive the different metastatic steps. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Review
Bone Density as a Marker of Response to Radiotherapy in Bone Metastatic Lesions: A Review of the Published Data
Int. J. Mol. Sci. 2016, 17(9), 1391; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091391 - 24 Aug 2016
Cited by 5 | Viewed by 2140
Abstract
Metastases to the bone are presenting in a great percentage of patients with cancer, causing a variety of symptoms, affecting the quality of life and survival of patients. A multidisciplinary approach from different health providers is required for treatment, including radiation oncologists, medical [...] Read more.
Metastases to the bone are presenting in a great percentage of patients with cancer, causing a variety of symptoms, affecting the quality of life and survival of patients. A multidisciplinary approach from different health providers is required for treatment, including radiation oncologists, medical oncologists and surgeons. The role of radiotherapy in the management of bone metastases has long been established through multiple randomized trials. The estimation of response to the therapy is subjective and is based on the palliation of the symptoms that the patients report. However, a quantification of the tumor burden and response to the treatment with the use of an objective method to measure those parameters is a clinical expectation in oncology. The change in bone density in affected areas (mainly lytic) after local radiotherapy, representing the cellular changes that have occurred, is a promising marker of response to treatment. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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Review
Bone Metastasis from Renal Cell Carcinoma
Int. J. Mol. Sci. 2016, 17(6), 987; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060987 - 22 Jun 2016
Cited by 33 | Viewed by 3274
Abstract
About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor [...] Read more.
About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor prognosis. Bone-targeted treatment using bisphosphonate and denosumab can reduce skeletal complications in RCC, but does not cure the disease or improve survival. Elucidating the molecular mechanisms of tumor-induced changes in the bone microenvironment is needed to develop effective treatment. The “vicious cycle” hypothesis has been used to describe how tumor cells interact with the bone microenvironment to drive bone destruction and tumor growth. Tumor cells secrete factors like parathyroid hormone-related peptide, transforming growth factor-β and vascular endothelial growth factor, which stimulate osteoblasts and increase the production of the receptor activator of nuclear factor κB ligand (RANKL). In turn, the overexpression of RANKL leads to increased osteoclast formation, activation and survival, thereby enhancing bone resorption. This review presents a general survey on bone metastasis in RCC by natural history, interaction among the immune system, bone and tumor, molecular mechanisms, bone turnover markers, therapies and healthcare burden. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
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