Site Directed Delivery of Chemotherapy and Non-Anticoagulant Sulfated Heparin in Breast Cancer

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5050-5050
Author(s):  
Shaker S Mousa ◽  
Dhruba Bahrali ◽  
Shaymaa S Mousa ◽  
Emmy Dier ◽  
Murat Yalcin ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Injection Site ◽  
Anticoagulant Activity ◽  
Hemoglobin Concentration ◽  
Chemotherapeutic Agents ◽  
Adhesion Assay ◽  
Significant Activity ◽  
Tumor Cell Adhesion ◽  
Highly Effective ◽  
Heparin Compounds

Abstract There is substantial literature support for the use of low molecular weight heparins (LMWH) for treating coagulation disorders in cancer patients. Recent prospective and retrospective clinical trials have also demonstrated that they provide significant advantages in terms of progression-free and overall survival in certain cancers and in certain subgroups of patients. LMWH treatments are often associated with increased bleeding, constituting a dose-limiting effect. We have developed novel non-anticoagulant heparin (NACH) compounds that have minimal effects on hemostasis (El-Naggar and Mousa, US Patents 6,908,907 B2, (2005), and 10, 667,216, (2003). We have evaluated them for efficacy vs. tumor growth and metastasis and have begun to investigate the mechanisms involved in anti-tumor activities. Modified sulfated LMWH with weak or no anticoagulant activities were still highly effective in inhibiting angiogenesis and metastasis, demonstrating that anticoagulation is not essential for attenuation of angiogenesis or metastasis. The modified heparins were characterized with respect to their ability to release endothelial tissue factor pathway inhibitor (TFPI) and inhibit selectin-mediated interactions, molecular components that have been shown to modulate tumor growth, tumor angiogenesis and metastasis. One of these modified heparin compounds that showed significant activity in a selectin-mediated tumor cell adhesion assay was also highly effective in reducing tumor burden in mice with MC-38 colon carcinoma and B16-BL6 melanoma (>70%) and in reducing the number of metastatic foci (>65%) in these animals. We also investigated the efficacy of NACH compounds on growth factor-induced angiogenesis in a mouse Matrigel model in which new vessel growth was quantified by measuring hemoglobin concentration extracted from the Matrigel plug. Values are Means ± SEM. Matrigel alone: 0.57± 0.12; bFGF + Matrigel: 7.27 ± 1.18; NAC-S-S: 0.86 ± 0.10. This sulfated compound which demonstrated no anticoagulant activity in aPTT and TEG assays, reduced capillary formation to baseline levels. These data demonstrate that non-anticoagulant heparin compounds exhibit a profile of anti-tumor activities without disrupting normal hemostasis. Site-directed therapy with non-anticoagulant heparins (NACH) and chemotherapy would allow for optimization of treatments in the tumor microenvironment. In studies that are currently underway, we are targeting the sites of tumor neovascularization using a biodegradable nanoparticulate system made up of a blend of MPEG-PLGA (methoxy-polyethyleneglycol-poly (lactide-co-glycolide) and maleimide-PEG-PLGA. These nanoparticles have their surfaces conjugated to alpha-v beta-3 antibody and contain chemotherapeutic agent Doxorubicin, with or without NACH. Preliminary data indicate that repeated administration of sulfated non-anticoagulant heparin compound at 10 mg/kg S.C. daily for up to 14 days in conjunction with doxorubicin caused no bruising at the injection site, whereas Enoxaparin showed injection site bruising in >50% of the mice. The use of NACH agents that are co-encapsulated with chemotherapeutic agents could minimize the toxic side effects of the chemotherapy while delivering a combination of effective therapeutic agents directly to the tumor.

scholarly journals Herbal Medicine Goshajinkigan Prevents Paclitaxel-Induced Mechanical Allodynia without Impairing Antitumor Activity of Paclitaxel

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Muh. Akbar Bahar ◽  
Tsugunobu Andoh ◽  
Keisuke Ogura ◽  
Yoshihiro Hayakawa ◽  
Ikuo Saiki ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Herbal Medicine ◽  
Tumor Growth ◽  
Mechanical Allodynia ◽  
Chemotherapeutic Agents ◽  
Antitumor Action ◽  
Effective Strategies ◽  
Anti Cancer ◽  
Mammary Fat Pad ◽  
4T1 Cells

Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of commonly used chemotherapeutic agents. However, there are no effective strategies to treat the neuropathy. We examined whether Goshajinkigan, a herbal medicine, would prevent paclitaxel-induced allodynia without affecting the anticancer action in mice. Murine breast cancer 4T1 cells were inoculated into the mammary fat pad. Paclitaxel (10 and 20 mg/kg, intraperitoneal, alternate day from day 7 postinoculation) inhibited the tumor growth, and Goshajinkigan (1 g/kg, oral, daily from day 2 postinoculation) did not affect the antitumor action of paclitaxel. Mechanical allodynia developed in the inoculated region due to tumor growth and in the hind paw due to paclitaxel-induced neuropathy. Paclitaxel-induced allodynia was markedly prevented by Goshajinkigan, although tumor-associated allodynia was not inhibited by Goshajinkigan. These results suggest that Goshajinkigan prevents paclitaxel-induced peripheral neuropathy without interfering with the anti-cancer action of paclitaxel.

scholarly journals Evaluation of Hyaluronic Acid to Modulate Oral Squamous Cell Carcinoma Growth In Vitro

2020 ◽  
Vol 11 (4) ◽  
pp. 72
Author(s):  
Jordan Ringer ◽  
Bryan Morrison ◽  
Karl Kingsley
Keyword(s):  
Growth Rate ◽  
Squamous Cell Carcinoma ◽  
Hyaluronic Acid ◽  
Oral Squamous Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
Chemotherapeutic Agents ◽  
Oral Tumor

Introduction: Previous studies have demonstrated that glycosaminoglycan hyaluronic acid (HA) is capable of mediating oral tumor growth. Some clinical evidence has suggested reduced HA expression predicts poor cancer prognosis and that HA-chemotherapy conjugates may function synergistically to inhibit oral tumor growth. Other studies have found conflicting results that suggest enhanced CD44-HA-mediated growth and proliferation. Due to the lack of clarity regarding HA function, the primary goal of this study was to investigate the effects of HA using well-characterized oral cancer cell lines. Methods: Using several commercially available oral squamous cell carcinoma lines (and a normal non-cancerous control), 96-well growth and viability assays were conducted using HA (alone and in combination with chemotherapeutic agents paclitaxel and PD98059). Results: Different results were observed in each of the cell lines evaluated. HA induced small, non-significant changes in cellular viability among each of the cell lines within a narrow range (1–8%), p = 0.207. However, HA induced differing effects on growth, with minimal, non-significant changes among some cell lines, such as SCC4 (+1.7%), CCL-30 (−2.8%), and SCC15 (−2.5%), p = 0.211 and more robust inhibition among other cell lines, SCC9 (−24.4%), SCC25 (−36.6%), and CAL27 (−47.8%), p = 0.0001. Differing effects were also observed with growth and viability under concomitant administration of HA with PD98059 or paclitaxel. Further analysis of these data revealed strong inverse (Pearson’s) correlations between initial baseline growth rate and responsiveness to HA administration, ranging from R = −0.27 to R = −0.883. Conclusion: The results of this study revealed differing responses to HA, which may be inversely correlated with intrinsic characteristics, such as the baseline growth rate. This may suggest that the more rapidly growing cell lines are more responsive to combination therapy with hyaluronic acid; an important finding that may provide insights into the mechanisms responsible for these observations.

scholarly journals Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Carlotta Pozza ◽  
Chiara Graziadio ◽  
Elisa Giannetta ◽  
Andrea Lenzi ◽  
Andrea M. Isidori
Keyword(s):  
Cushing’S Syndrome ◽  
Somatostatin Receptor ◽  
Cushing's Syndrome ◽  
Chemotherapeutic Agents ◽  
Peroxisome Proliferator ◽  
Significant Activity ◽  
Ectopic Acth ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ectopic Acth Secretion ◽  
Free Cortisol

Cushing’s syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing’s disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone “RU-486”). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptorγ“PPAR-γ” ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors.

Clinical Efficacy of VEL-CTD (Bortezomib, Cyclophosphamide, Thalidomide, and Dexamethasone) Regimen in Patients with Relapsed or Refractory Multiple Myeloma: A Phase II Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3693-3693
Author(s):  
Yeo-Kyeoung Kim ◽  
Je-Jung Lee ◽  
Sang-Kyun Sohn ◽  
Ho-Jin Shin ◽  
Joo-Seop Chung ◽  
...  
Keyword(s):  
Sensory Neuropathy ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Complete Response ◽  
Median Number ◽  
Chemotherapeutic Agents ◽  
Significant Activity ◽  
Treatment Regimens ◽  
Highly Active ◽  
Therapeutic Responses

Abstract BACKGROUND: Recent studies demonstrates that the combination of bortezomib and several chemotherapeutic agents may have significant activity in myeloma. In this study, we assessed the efficacy and safety of the combination with bortezomib, cyclophosphamide, thalidomide, and dexamethasone (vel-CTD) for the patients with relapsed/refractory myeloma. METHODS: Fifty-three patients who had received at least four cycles of treatment were enrolled. Bortezomib was given at 1.3 mg/m2 on D1, 4, 8, 11, thalidomide 50 mg/day, daily, cyclophosphamide 150 mg/m2 P.O. on D1–4, and dexamethasone 20 mg/m2 I.V. or P.O. on D1, 4, 8, 11. RESULTS: There were 26 males (49.1%) and 27 females (50.9%). The median age of patients was 67 years (range, 40–78 years). Median number of the previous treatment regimens was two (range, 1~5). Of total 53 patients, forty-nine patients (92.5%) achieved at least a partial response (PR) including 28 (52.8%) with complete response (CR) and 21 (42.9%) with PR as their best response. Median progression-free survival (PFS) was 14.7 months (range; 12.3–17.1 months) and median overall survival (OS), from the onset of vel-CTD was 31.6 months (range; 23.3–39.9 months). Patients who achieved a good response at least a PR after four cycles of vel-CTD showed longer PFS than those with poor therapeutic responses (2yr PFS, 28±8.7% vs. 0%, p=0.03). Further, patients who achieved a good therapeutic responses also showed significantly longer OS than those with poor responses (2yr OS, 72.3±8.3% vs. 33.3±15.7%, p=0.009). Grade 3–4 toxicities included thrombocytopenia (30.2%), neutropenia (11.3%), peripheral sensory neuropathy (32.1%), and thrombosis (3.8%). There was no treatment-related death. CONCLUSIONS: Vel-CTD is a highly active salvage therapy in patients with relapsed/refractory myeloma. However, frequent side effects such as peripheral neuropathy should be considered. Furthermore, trials evaluating novel treatment approaches after bortezomib should be offered to reduce the rate of disease progression, particularly in patients who fail to show a good response at least PR after four cycles of therapy.

LFB-R603, a Third-Generation Monoclonal Anti-CD20 Antibody Displays An Additive Antitumor Activity with Antileukemic Chemotherapeutic Agents in Mouse Xenograft Models

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1660-1660 ◽  
Author(s):  
Isabel Tourais Esteves ◽  
Charles Dumontet ◽  
Stéphanie Herveau ◽  
Lina Reslan ◽  
Frédérique Brune ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Mantle Cell Lymphoma ◽  
Subcutaneous Injection ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Mantle Cell ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Abstract 1660 LFB-R603, a next generation anti-CD20 antibody currently in clinical development, is characterized by a specific glycosylation pattern containing a high percentage of non fucosylated antibodies molecules at the Fc site. This pattern of glycosylation increases the affinity of antibodies for human FcγRIIIa, resulting in an increased antibody dependent cell-mediated cytotoxicity (ADCC) by human FcγRIIIa-expressing effector cells. This antibody is currently in a phase I clinical trial in B-CLL patients and its use is planned to be expanded to other non-hodgkin's lymphomas (NHL) such as follicular and mantle cell lymphoma, as a single agent and in combination with chemotherapeutic agents. The antitumor efficacy of LFB-R603 was studied in comparison with rituximab in combination with conventional chemotherapeutic agents in two models of NHL developed in immuno-deficient mice. The RL cell line, derived from a patient with follicular lymphoma (FL), was xenografted in mice by subcutaneous injection. Tumor-bearing mice were treated intravenously during 4 weeks with the anti-CD20 antibodies used alone or in combination with suboptimal doses of cyclophosphamide 50 mg/kg or bendamustine 30 mg/kg. LFB-R603 and rituximab displayed a dose-related antitumor activity. The tumor growth inhibition (TGI) was at day 30, 64% at 10 mg/kg, 84% at 30 mg/kg and 100% at 100 mg/kg for LFB-R603 compared with the untreated-group. For rituximab, the TGI was 84% at 30 mg/kg and 99% at 100 mg/kg. More interestingly, LFB-R603 at 100 mg/kg dose showed a significantly superior antitumor activity as a delay of 21 days in tumor growth was observed compared to rituximab (p=0.00001). The combination of LFB-R603 or rituximab at 60 mg/kg with cyclophosphamide enhanced the effect observed with the antileukemic agent only and the additive effect was similar for the two antibodies as a delay of 13 days in tumor growth was observed for both combination-treated groups compared with the cyclophosphamide-treated group (p=0.00001). However, LFB-R603 displayed a significant higher antitumor activity against RL xenografts than rituximab when combined with bendamustine as a tumor growth delay of 7 days was observed between the two treated-groups (p=0.00001). The NCEB cell line, derived from a patient with mantle cell lymphoma (MCL), was xenografted in mice by subcutaneous injection. In this model, LFB-R603 and rituximab injected once weekly up to 3 weeks displayed a dose-related TGI activity. A higher activity of LFB-R603 compared to rituximab was observed at all tested doses (3, 10, 30 and 60 mg/kg). TGI values at day 51 were 91% for LFB-R603 at 3 mg/kg versus 40% for rituximab, 88% for LFB-R603 at 10 mg/kg versus 57 % for rituximab and 100% for LFB-R603 at 30 and 60 mg/kg versus 66% for rituximab when compared with untreated-group. In conclusion, LFB-R603 displayed a greater antitumor activity as compared to rituximab in two different non-clinical in vivo models of NHL, namely follicular and mantle cell lymphoma. Moreover, additive effects were obtained when LFB-R603 was combined with chemotherapeutic agents such as cyclophosphamide and bendamustine in the FL model. Disclosures: Tourais Esteves: LFB Biotechnologies: Employment. Dumontet:LFB Biotechnologies: Research Funding. Herveau:LFB Biotechnologies: Research Funding. Reslan:LFB Biotechnologies: Research Funding. Brune:LFB Biotechnologies: Employment. Van Overtvelt:LFB Biotechnologies: Employment. Salcedo:LFB Biotechnologies: Employment. Fournès:LFB Biotechnologies: Employment.

Causes and Consequences of Cancer-Associated Thrombocytosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-33-SCI-33
Author(s):  
Anil Sood ◽  
Rebecca L. Stone ◽  
Vahid Afshar-Kharghan
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Epithelial Ovarian Cancer ◽  
Mouse Models ◽  
Interleukin 6 ◽  
Conflicts Of Interest ◽  
Chemotherapeutic Agents ◽  
Antibody Treatment ◽  
Platelet Counts ◽  
Tumor Bearing

Abstract Platelets represent one of the largest storage pools of angiogenic and oncogenic growth factors in the human body. The observation that thrombocytosis (platelet count >450,000/µL) occurs in patients with solid malignancies was made over 100 years ago. However, mechanisms of paraneoplastic thrombocytosis and the role that platelets play in abetting cancer growth are unclear. We have used clinical data coupled with sophisticated mouse models to identify the mechanisms and biological implications of paraneoplastic thrombocytosis. Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti-interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an anti-platelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. Biologically, platelets were detected within the tumor microenvironment and affected tumor growth and response to chemotherapeutic agents. These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. Blocking the stimulatory effects of platelets may have implications for new therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

Cisplatin chemotherapy in the treatment of BRCA1-positive metastatic breast cancer (MBC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1099-1099 ◽  
Author(s):  
T. Byrski ◽  
M. Foszczynska-Kloda ◽  
T. Huzarski ◽  
R. Dent ◽  
J. Gronwald ◽  
...  
Keyword(s):  
Antitumour Activity ◽  
Brca1 Mutation ◽  
Performance Status ◽  
Metastatic Breast ◽  
Chemotherapeutic Agents ◽  
Phase Iii ◽  
Institutional Review Boards ◽  
Prior History ◽  
Significant Activity ◽  
Metastatic Setting

1099 Background: Preclinical data suggest that women with BRCA1 related breast cancers may be particularly sensitive to chemotherapeutic agents that cause DNA damage such as cisplatin chemotherapy. This study was conducted to assess the efficacy and safety of cisplatin chemotherapy in patients with BRCA1 positive MBC. Methods: This was a multicenter, open label, single arm study of cisplatin 75 mg/m2 given intravenously every three weeks until disease progression or toxicity. The primary objective was to assess antitumour activity of cisplatin, as measured by clinical benefit response (CR, PR, or SD ≥ 6 months). Eligible patients had locally recurrent or MBC, had 0–2 prior chemotherapy regimens in the metastatic setting, and had received prior therapy with an anthracycline. Patients were restaged every eight weeks. The study protocol was approved by the institutional review boards of participating institutions. Results: A total of 15 patients were enrolled. Mean age was 48.1 years (range: 32 to 70). ECOG performance status scores were 0 (6 pts), 1 (5 pts), 2 (4 pts). All patients had a confirmed BRCA1 mutation (7 with C61G mutation, 7 with 5382 insC, 1 with 4153delA). Five patients (33%) were ER or PR + and none were HER-2+. Prior history of MBC chemotherapy included 1 regimen (4 pts) and 2 regimens (7 pts). Seven (46%) and 4 (26%) patients had complete and partial responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, for an overall response rate of 72%. Median duration of response has not yet been reached. In general, cisplatin was well tolerated. Neutropenia was the commonest toxicity with 33% grade 2 (6,7% and 0%, grades 3 and 4 neutropenia). No patients developed febrile neutropenia. Conclusions: Significant activity and favorable toxicity profile provides a basis for considering cisplatin for further evaluation in phase III trials for women with BRCA1 positive MBC. No significant financial relationships to disclose.

scholarly journals SOX4 promotes the growth and metastasis of breast cancer

2020 ◽  
Author(s):  
Jing Zhang ◽  
Chunhua Xiao ◽  
Zhenbo Feng ◽  
Yun Gong ◽  
Baohua Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Lymph Nodes ◽  
Cell Viability ◽  
Cancer Cell ◽  
Chemotherapeutic Agents ◽  
Migration And Invasion ◽  
Primary Tumors

Abstract Purpose Increasing evidence has shown that the transcription factor SOX4 is closely associated with the development and progression of many malignant tumors. However, the effect of SOX4 on breast cancer is unclear. In this study, we purposed to investigate the role of SOX4 in the growth and metastasis in breast cancer and the underlying mechanism. Moreover, the effect of SOX4 on cancer cell resistance to chemotherapeutic agents was also evaluated in vitro and in vivo . Methods We used lentivirus technique to ectopically express SOX4 in MDA-MB-231 and SUM149 cells or knockdown SOX4 in BT474 cells, and examined the effect of these changes on various cellular functions. MTT assay was used to determine the cell viability as well as resistance to chemotherapeutic agents. The regulation of SOX4 on epithelial-mesenchymal transition (EMT)-related genes was analyzed using qRT-PCR. The binding of SOX4 to the CXCR7 gene was demonstrated using chromatin immunoprecipitation assay and dual-luciferase reporter activity assay. The effect of SOX4/CXCR7 axis on metastasis was examined using Transwell migration and Matrigel invasion assays. The expression of SOX4/CXCR7 in primary tumors and metastatic foci in lymph nodes was assessed using immunohistochemistry. Cellular morphology was investigated under phase contrast microscope and transmission electron microscopy. Moreover, the effect of SOX4 on tumor growth, metastasis, and resistance to chemotherapy was also studied in vivo by using bioluminescent imaging. Results SOX4 increased breast cancer cell viability, migration, and invasion in vitro and enhanced tumor growth and metastasis in vivo . It regulated EMT-related genes and bound to CXCR7 promoter to upregulate CXCR7 transcription. Both SOX4 and CXCR7 were highly expressed in human primary tumors and metastatic foci in lymph nodes. Treatment of breast cancer cells with the CXCR7 inhibitor CCX771 reversed the SOX4 effect on cell migration and invasion. Ectopic expression of SOX4 increased the susceptibility of cells to paclitaxel. Conclusions SOX4 plays an important role in the growth and metastasis of breast cancer. SOX4/CXCR7 may serve as potential therapeutic targets for the treatment. Paclitaxel may be a good therapeutic option if the expression level of SOX4 is high.

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