Osteogenic Activity of Yellow Flag Iris (Iris pseudacorus) Extract Modulating Differentiation of Osteoblasts and Osteoclasts

2012 ◽  
Vol 40 (06) ◽  
pp. 1289-1305 ◽  
Author(s):  
Jung-Lye Kim ◽  
Hong Mei Li ◽  
Yun-Ho Kim ◽  
Yong-Jin Lee ◽  
Jae-Hoo Shim ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Phosphatase Activity ◽  
Bone Diseases ◽  
Nodule Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Raw 264.7 ◽  
Type I ◽  
Metabolic Bone Diseases ◽  
Yellow Flag

Bone integrity is maintained through a balance between bone formation by osteoblasts and bone resorption by osteoclasts. Imbalance of the process results in metabolic bone diseases such as osteoporosis. This study investigated the yellow flag iris extract (YFIE) and revealed its anti-osteoporotic effects in osteoblastic MC3T3-E1 mouse cells and RAW 264.7 murine macrophages. When osteoblasts were treated with 1–20 μg/ml YFIE in an osteogenic medium, the bone nodule formation by calcium deposits was markedly enhanced during differentiation. Consistently, YFIE stimulated alkaline phosphatase activity and collagen type I secretion with a substantial effect on osteoblast proliferation. On the other hand, RAW 264.7 macrophages were pre-incubated with 1–20 μg/ml YFIE for 5 days in the presence of receptor activator of nuclear factor-κB ligand (RANKL). Non-toxic YFIE markedly attenuated the differentiation of macrophages to multi-nucleated osteoclasts. YFIE diminished RANKL-elevated tartrate-resistant acid phosphatase activity and bone resorption. In addition, the YFIE treatment retarded RANKL-induced cathepsin K production and carbonic anhydrase II expression, both of which are involved in bone resorption. Therefore, YFIE potentially posesses therapeutic agents that may prevent osteoporosis through promoting bone formation and reducing bone resorption.

Bortezomib Reduces Serum Dickkopf-1 and RANKL Concentrations and Normalizes Indices of Bone Remodeling in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 506-506
Author(s):  
Evangelos Terpos ◽  
Deborah Heath ◽  
Amin Rahemtulla ◽  
Kostas Zervas ◽  
Andrew Chantry ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Remodeling ◽  
Serum Levels ◽  
Response To Therapy ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Lytic Lesions ◽  
Tracp 5B ◽  
Dickkopf 1

Abstract Bortezomib is a proteasome inhibitor, which is currently indicated for the treatment of relapsed/refractory myeloma (MM). Although the anti-myeloma effect of bortezomib has been clearly demonstrated, its effect on bone metabolism is still unclear. There are recent reports that bortezomib increases serum alkaline phosphatase (ALP) activity, which is consistent with enhanced osteoblast function. The aim of this study was to evaluate the effect of bortezomib on bone turnover in 34 patients with relapsed MM. Bortezomib was given alone at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle for 4 cycles. Responders could continue for 4 more cycles, while non-responders could continue therapy with the addition of dexamethasone. The following serum indices were measured on day 1 of cycle 1, and then on day 21 of cycles 4 and 8: osteoblast inhibitor dickkopf-1 (DKK-1); osteoclast regulators: soluble RANKL (sRANKL) and osteoprotegerin (OPG); bone resorption markers: C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase type-5b (TRACP-5b); and bone formation markers: bone-specific ALP (bALP) and osteocalcin (OC). We also studied 33 healthy controls of similar gender and age. The objective response rate after 4 cycles of therapy was 66%: CR 8% and PR 58%. Sixteen responders and 3 non-responders continued on therapy for 4 more cycles. Myeloma patients at baseline had increased values of DKK-1 (p=0.007), sRANKL, sRANKL/OPG ratio, and both markers of bone resorption (p<0.0001) when compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p<0.001). There was a strong correlation between bone lytic disease and serum CTX (r=0.59, p<0.01), and sRANKL (r=0.4, p=0.03). Patients with severe bone disease (>9 lytic lesions, n=7) had elevated values of DKK-1 compared with all others (mean±SD: 223.4±264.4 ng/mL vs. 84±62.4 ng/mL; p=0.01). Moreover, serum levels of DKK-1 correlated with CTX levels (r=0.39, p=0.04), and weakly with bALP concentrations (r=−0.32, p=0.09). The administration of bortezomib produced a significant reduction of DKK-1 (p=0.035), sRANKL (p=0.01), CTX and TRACP-5b (p<0.001) after 4 cycles, which was still seen after 8 cycles of treatment (p<0.01). Bortezomib also produced a dramatic increase in both markers of bone formation, bALP and OC, after 4 and 8 cycles of therapy (p<0.01). Responders tended to have lower initial levels of DKK-1 compared with non-responders. Patients who achieved a CR or vgPR after 4 cycles of bortezomib had greater elevation of bALP than all others: mean±SD of increase: 306.3%±556.9% vs. 45.8%±56.5%; p=0.02. It is of interest that 3/4 non responders also had an increase in bALP (mean: 39.6%) after 4 cycles of bortezomib. There was no other correlation between response to therapy and alteration of bone markers. No healing of the lytic lesions was observed even in CR patients. This study suggests that bortezomib reduces serum levels of DKK-1 and RANKL, irrespective of response to therapy, in patients with relapsed myeloma and thus leads to normalization of abnormal bone remodeling through the increase of bone formation and reduction of bone resorption.

scholarly journals Collagen fragments in urine derived from bone resorption are highly racemized and isomerized: a biological clock of protein aging with clinical potential

2000 ◽  
Vol 345 (3) ◽  
pp. 473-480 ◽  
Author(s):  
Paul A. C. CLOOS ◽  
Christian FLEDELIUS
Keyword(s):  
Bone Resorption ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Bone Diseases ◽  
Bone Collagen ◽  
Type I ◽  
Bovine Bone ◽  
Metabolic Bone Diseases ◽  
T Score ◽  
Age Related

Fragments of the α1 C-terminal telopeptide of type I collagen containing the sequence AHDGGR1209-1214 (CTx) can be measured in urine as an index of bone resorption. We report here that these molecules undergo racemization and isomerization of Asp1211in vitro and in vivo, generating a mixture of four isomers: the native peptide form (αL), an isomerized form containing a β-Asp bond (βL), a racemized form containing a D-Asp residue (αD) and an isomerized/racemized form (βD). To study these reactions at this specific site in collagen, we have employed four immunoassays, each specific for one of the isoforms, and developed HPLC methods for their separation. The kinetics of these reactions were studied in vitro under physiological conditions by incubation of synthetic AHDGGR hexapeptide or mineralized bone collagen. Reactions were found to be strongly shifted towards the β-Asp forms and slightly in favour of the D-enantiomeric forms. CTx isomers were measured in human urine and in enzymic digests of bovine bone collagen. The results indicated that the extent of racemization and isomerization were correlated with the age and turnover of collagen. The ratios between the native and age-related forms of CTx were elevated in urine from patients with Paget's disease or osteoporosis as compared with that from healthy adults. The αL/αD CTx ratio had the highest discriminatory power (T-score = 23.2; P < 0.0001 and T-score = 1.5; P < 0.0001 for Paget's disease and osteoporosis respectively). In conclusion, these findings indicate that an assessment of CTx ratios in urine may provide an estimate of bone turnover, aiding in the diagnosis of metabolic bone diseases.

scholarly journals Serum N-Terminal Propeptide of Collagen Type I is Associated with the Number of Bone Metastases in Breast and Prostate Cancer and Correlates to Other Bone Related Markers

2011 ◽  
Vol 3 ◽  
pp. BIC.S6484 ◽  
Author(s):  
D.J. Leeming ◽  
M. Koizumi ◽  
P. Qvist ◽  
V. Barkholt ◽  
C. Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metastases ◽  
Cancer Patients ◽  
Collagen Type ◽  
Collagen Type I ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Breast And Prostate Cancer

Background A number of biomarkers have been proven potentially useful for their ability to indicate bone metastases (BM) in cancer patients. The aim of this study was to investigate the relative utility of a newly developed N-terminal propeptide of collagen type I (PINP) human serum assay for the detection of BM in cancer patients. This assay has a corresponding rat PINP assay which in the future might help in translational science between rodent and human trials. Methods Participants were 161 prostate, lung and breast cancer patients stratified by number of BM(Soloway score). PINP was assessed and correlated to number of BM. Additionally, the PINP marker was correlated to bone resorption of young (ALPHA CTX-I)- and aged bone (BETA CTX-I); number of osteoclasts (Tartrate-resistant acid phosphatase 5b, TRACP5B) and osteoclast activity (CTX-I/TRACP5B). Results PINP was significantly elevated in breast- and prostate cancer patients +BM, compared to –BM ( P < 0.001), however not in lung cancer patients. A strong linear association was seen between PINP and the number of BMs. Significant elevation of PINP was observed at Soloway scores 1–4 (<0 BM) compared with score 0 (0 BM) ( P < 0.001). The correlation between bone resorption of young bone or aged bone and bone formation was highly significant in patients +BM and –BM ( P < 0.0001). Conclusions Data suggest that the present PINP potentially could determine skeletal involvement in patients with breast or prostate cancer. Correlations suggested that coupling between bone resorption and bone formation was maintained in breast- and prostate cancer patients.

scholarly journals The Importance of the Prenyl Group in the Activities of Osthole in Enhancing Bone Formation and Inhibiting Bone ResorptionIn Vitro

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Yuan-Kun Zhai ◽  
Ya-Lei Pan ◽  
Yin-Bo Niu ◽  
Chen-Rui Li ◽  
Xiang-Long Wu ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Phosphatase Activity ◽  
Osteoporosis Treatment ◽  
Bone Morphogenetic Protein 2 ◽  
Tartrate Resistant Acid Phosphatase ◽  
Protective Effects ◽  
Morphogenetic Protein ◽  
Enhanced Secretion ◽  
Related Transcription Factor

Osteoporosis treatment always aimed at keeping the balance of bone formation and bone resorption. Recently, prenyl group in natural products has been proposed as an active group to enhance the osteogenesis process. Osthole has both the prenyl group and bone-protective activities, but the relationship is still unknown. In this study we found that osthole exerted a potent ability to promote proliferation and osteogenic function of rat bone marrow stromal cells and osteoblasts, including improved cell viability, alkaline phosphatase activity, enhanced secretion of collagen-I, bone morphogenetic protein-2, osteocalcin and osteopontin, stimulated mRNA expression of insulin-like growth factor-1, runt-related transcription factor-2, osterix, OPG (osteoprotegerin), RANKL (receptor activator for nuclear factor-κB ligand), and the ratio of OPG/RANKL, as well as increasing the formation of mineralized nodules. However, 7-methoxycoumarin had no obvious effects. Osthole also inhibited osteoclastic bone resorption to a greater extent than 7-methoxycoumarin, as shown by a lower tartrate-resistant acid phosphatase activity and lower number and smaller area of resorption pits. Our findings demonstrate that osthole could be a potential agent to stimulate bone formation and inhibit bone resorption, and the prenyl group plays an important role in these bone-protective effects.

SB431542, a TGF-Beta Receptor Kinase Inhibitor, Restores Bone Formation Which Ameliorates Myeloma-Induced Microenvironment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3479-3479 ◽  
Author(s):  
Kyoko Takeuchi ◽  
Masahiro Abe ◽  
Asuka Oda ◽  
Hiroe Amou ◽  
Masahiro Hiasa ◽  
...  
Keyword(s):  
Cell Growth ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Nodule Formation ◽  
Type I ◽  
Receptor Kinase ◽  
Tgf Beta ◽  
The Impact

Abstract Multiple myeloma (MM) cells stimulate bone resorption and concomitantly suppress bone formation, leading to devastating bone destruction. TGF-beta, a potent inhibitor for terminal osteoblasts (OB) maturation and mineralization, is abundantly produced and released from bone tissues through enhanced bone resorption, and activated by osteoclasts (OC)-derived acids and MMPs in MM bone lesions. In the present study we investigated the impact of TGF-beta inhibition on induction of bone formation in MM as well as the effects of matured OB on MM growth. TGF-beta completely suppressed BMP-2-induced mineralized nodule formation by OB cultured in osteogenic media supplemented with beta-glycerophosphate and vitamin C. SB431542, an inhibitor of TGF-beta type I receptor kinase, potently suppressed induction of Smad6 by TGF-beta, which inhibits BMP-2 signaling. SB431542 along with BMP-2 abolished such TGF-beta actions and enhanced mineralized nodule formation more than BMP-2 alone. Notably, addition of SB431542 antagonized the inhibitory effects of conditioned media from MM cell lines (RPMI8226 and U266) and bone marrow plasma from patients with MM, resulting in restoration of the BMP-induced mineralized nodule formation. Furthermore, MC3T3-E1 cells matured by BMP-2 enough to exhibit mineralized nodules suppressed the proliferation of 5TGM1 MM cells in sharp contrast to stromal cells as well as untreated or TGF-beta-treated undifferentiated MC3T3-E1 cells that promote MM cell growth and survival. Interestingly, 5TGM1 MM cell growth was also potently suppressed by MC3T3-E1 cells cultured with BMP-2 in the absence of beta-glycerophosphate to achieve OB maturation without formation of mineralized nodules, suggesting a responsible role for OB-derived non-mineralized factors associated with terminal differentiation of OB. In addition, the induction of OB maturation down-regulated the production by OB of IL-6 and up-regulated osteoprotegerin, an inhibitor for osteoclastogenesis. Taken together, blockade of TGF-beta actions release OB from the differentiational arrest in MM bone disease and thus can be a good therapeutic maneuver restoring bone formation as well as suppressing osteoclastogenesis to ameliorate bone destruction and at the same time suppressing MM expansion by disrupting the MM-induced microenvironment which can be called as MM niche.

Edgeworthia papyrifera Regulates Osteoblast and Osteoclast Differentiation In Vitro and Exhibits Anti-osteoporosis Activity in Animal Models of Osteoporosis

Planta Medica ◽  
2019 ◽  
Vol 85 (09/10) ◽  
pp. 766-773 ◽  
Author(s):  
Pansoo Kim ◽  
Yeon-Ju Nam ◽  
Woo Jung Kim ◽  
Jin Kyu Kim ◽  
Gyeongbeen Lee ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Animal Models ◽  
Osteoclast Differentiation ◽  
Raw 264.7 Cells ◽  
Tartrate Resistant Acid Phosphatase ◽  
Raw 264.7 ◽  
Treatment Of Osteoporosis ◽  
Increased Risk ◽  
Interesting Candidate

AbstractOsteoporosis is a clinical condition characterized by low bone strength that leads to an increased risk of fracture. Strategies for the treatment of osteoporosis involve inhibition of bone resorption by osteoclasts and an increase of bone formation by osteoblasts. Here, we identified the extract derived from the stem part of Edgeworthia papyrifera that enhanced differentiation of MC3T3-E1 cells to osteoblast-like cells and inhibited osteoclast differentiation of RAW 264.7 cells in vitro. In support of our observation, rutin and daphnoretin, which were previously reported to inhibit osteoclast differentiation, were identified in E. papyrifera extract. In an animal model of osteoporosis, the ovariectomy-induced increases in bone resorption biomarkers such as pyridinoline and tartrate-resistant acid phosphatase were significantly reduced by E. papyrifera extract administration at 25.6 and 48.1%, respectively. Furthermore, the ovariectomy-induced bone loss in animal models of osteoporosis was significantly prevented by the administration of E. papyrifera in our study. Taking these observations into account, we suggest that E. papyrifera is an interesting candidate for further exploration as an anti-osteoporotic agent.

Different responses of biochemical markers of bone resorption to bisphosphonate therapy in Paget disease

1995 ◽  
Vol 41 (11) ◽  
pp. 1592-1598 ◽  
Author(s):  
A Blumsohn ◽  
K E Naylor ◽  
A M Assiri ◽  
R Eastell
Keyword(s):  
Bone Resorption ◽  
Biochemical Markers ◽  
Type I Collagen ◽  
Bisphosphonate Therapy ◽  
Response To Therapy ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Paget Disease ◽  
Markers Of Bone Resorption ◽  
Total Alkaline

Abstract We examined the response of different biochemical markers of bone resorption to bisphosphonate therapy (400 mg of etidronate daily for 6 months) in mild Paget disease (n = 14). Urinary markers included hydroxyproline (OHP), total (T) and free (F) pyridinolines (Pyds) determined by HPLC, immunoreactive FPyds, immunoreactive TPyds, and the N- and C-terminal telopeptides of type I collage (NTx, CL). Serum measurements included tartrate-resistant acid phosphatase (TRAcP) and the C-terminal telopeptide of type I collagen (ICTP). ICTP and TRAcP showed a minimal response to therapy (% change at 6 months, -13.1 +/- 6.8 and -6.7 +/- 3.4, respectively). The response was greatest for urinary telopeptides (NTx and CL; % change -75.7 +/- 7.5 and -73.4 +/- 8.9, respectively). The response was somewhat greater for TPyds than for FPyds. We conclude that: (a) ICTP and TRAcP are unreliable indicators of changes in bone turnover; (b) oligopeptide-bound Pyds and telopeptide fragments of type I collagen in urine show a somewhat greater response to therapy than do FPyds and may be more sensitive indicators of bone resorption; and (c) as yet no evidence suggests that these markers are substantially better predictors of the clinical response to therapy than serum total alkaline phosphatase or urinary OHP. There are several problems with the interpretation of these measurements in Paget disease, and the clinical utility of these measurements remains uncertain.

scholarly journals Bisphosphonates in the treatment of metabolic bone diseases

2010 ◽  
Vol 54 (2) ◽  
pp. 206-212 ◽  
Author(s):  
Henrique Pierotti Arantes ◽  
André Gonçalves da Silva ◽  
Marise Lazaretti-Castro
Keyword(s):  
Bone Resorption ◽  
Bone Diseases ◽  
Low Bone Mass ◽  
Metabolic Bone Diseases ◽  
Treatment Of Osteoporosis ◽  
Good Safety Profile ◽  
Metabolic Bone ◽  
Prevention And Treatment ◽  
High Bone ◽  
Osteonecrosis Of Jaw

Osteoporosis is a disease characterized by low bone mass associated with the deterioration of microarchitecture, due to an imbalance either in high bone resorption or low bone formation or in both, leading to a high risk of fractures. Bisphosphonates are medications which reduce the ability of osteoclasts to induce bone resorption and consequently improve the balance between resorption and formation. There are bisphosphonates approved for the prevention and treatment of osteoporosis. Administration can be oral (daily, weekly or monthly) or intravenous (quarterly or yearly). These medications are well tolerated and with the correct instructions of administration have a good safety profile. Serious side effects, such as, osteonecrosis of jaw is very rare. Bisphosphonates are the most prescribed medication for the treatment of osteoporosis.

scholarly journals Novel Metabolic Pathways Associated with Serum Bone Turnover Markers in Healthy Young Adults

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 71-71
Author(s):  
Joseph Roberts ◽  
Moriah Bellissimo ◽  
Kaitlin Taibl ◽  
Karan Uppal ◽  
Dean Jones ◽  
...  
Keyword(s):  
Young Adults ◽  
Fatty Acid ◽  
Amino Acid ◽  
High Resolution ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Turnover ◽  
Metabolic Pathways ◽  
Type I ◽  
Turnover Markers

Abstract Objectives Optimal bone health is maintained through a remodeling cycle consisting of resorption followed by formation. Procollagen type I N-terminal propeptide (P1NP) and C-terminal telopeptides of type I collagen (CTX) are biomarkers of bone metabolism that capture changes in bone formation and bone resorption, respectively. This study aimed to identify unique metabolic pathways related to bone turnover markers (BTMs) in healthy young adults. Methods This cross-sectional study included 34 healthy, young adults (19 females, average age 27.8 years). Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry. Fasting plasma was analyzed using dual column liquid chromatography and ultra-high-resolution mass spectrometry for metabolomics. Serum levels of P1NP and CTX were measured with ELISA. Linear regression and pathway enrichment analyses were used to identify metabolic pathways related to the BTMs. Results All participants had a normal whole-body BMD T-score. Metabolites significantly associated with P1NP (at P &lt; 0.05) were significantly enriched in pathways linked to the TCA cycle, pyruvate metabolism, and metabolism of B-vitamins important for energy production (e.g., niacin, thiamin). Other nutrition-related metabolic pathways associated with P1NP were amino acid (proline, arginine, glutamate) and vitamin C metabolism, which are important for collagen formation. Metabolites were associated with CTX levels (at P &lt; 0.05), which were enriched within lipid and fatty acid beta-oxidation metabolic pathways, as well as fat soluble micronutrients pathways including, vitamin D metabolism, vitamin E metabolism, and bile acid biosynthesis. Conclusions High-resolution metabolomics identified several distinct plasma metabolic pathways, including energy-yielding metabolic pathways and pathways related to fatty acid, amino acid, and micronutrient metabolism that were associated with markers of bone formation and bone resorption. Characterizing these metabolism-related pathways associated with BTMs in healthy adults is an important step towards understanding the metabolic perturbations that lead to low bone mass in older and clinical populations. Funding Sources National Institutes of Health and Emory University.

scholarly journals Osteopontin deficiency enhances anabolic action of EP4 agonist at a sub-optimal dose in bone

2007 ◽  
Vol 193 (1) ◽  
pp. 171-182 ◽  
Author(s):  
Norihiko Kato ◽  
Keiichiro Kitahara ◽  
Susan R Rittling ◽  
Kazuhisa Nakashima ◽  
David T Denhardt ◽  
...  
Keyword(s):  
Bone Formation ◽  
Optimal Dose ◽  
Bone Diseases ◽  
Mineral Apposition Rate ◽  
Modern World ◽  
Nodule Formation ◽  
Prostaglandin E ◽  
Anabolic Agents ◽  
Bone Formation Rate ◽  
Anabolic Action

Osteoporosis is one of the most widespread and destructive bone diseases in our modern world. There is a great need for anabolic agents for bone which could reverse this disease, but few are available for clinical use. Prostaglandin E receptor (EP4) agonist (EP4A) is one of the very few anabolic agents for bone in rat, but its systemic efficacy against bone loss at sub-optimal dose is limited in mice. As osteoblasts are regulated by extracellular matrix proteins, we tested whether deficiency of osteopontin (OPN), a secreted phosphorylated protein, could modulate the effects of EP4A (ONO-AE1-329) treatment at 30 μg/kg body weight, a sub-optimal dose, for 5 days/week for 4 weeks. OPN deficiency enhanced the anabolic effects of EP4A on bone volume. Histomorphometric analysis indicated that EP4A increased mineral apposition rate as well as bone formation rate in OPN-deficient but not in wild-type mice. Neither OPN deficiency nor EP4A altered osteoclast parameters. Importantly, OPN deficiency enhanced the direct anabolic action of EP4A locally injected onto the parietal bone in inducing new bone formation. Combination of OPN deficiency and EP4A treatment caused an increase in mineralized nodule formation in the cultures of bone marrow cells. Finally, OPN deficiency enhanced anabolic action of EP4A in the mice subjected to ovariectomy. These data indicate that OPN deficiency enhances the actions of EP4A at sub-optimal dose.

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