Photo of Markus H. Frank,   M.D.

Markus H. Frank, M.D.

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 919-2993
Fax: (617) 730-0129


Markus.Frank@childrens.harvard.edu

Markus H. Frank, M.D.

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Associate Professor, Pediatrics, Harvard Medical School
  • Associate Professor, Dermatology, Harvard Medical School
  • Associate Physician, Medicine, Brigham And Women's Hospital
  • Member, Stem Cell Program, Boston Children's Hospital
  • Co-Leader, Skin Program, HARVARD STEM CELL INSTITUTE - HSCI

DF/HCC PROGRAM AFFILIATION

Research Abstract

Dr. Frank's laboratory research, conducted in the Transplantation Research Program of Boston Children's Hospital and the Department of Dermatology at Brigham and Women's Hospital, focuses on the physiological and pathological roles of the human P-glycoprotein family of ATP-binding cassette (ABC) transporters.

His laboratory has cloned and characterized a novel human P-glycoprotein family member, ABCB5, which regulates maintenance and differentiation of normal tissue-specific stem cells with therapeutic capacity as a transplantable cell source for immunomodulation (Schatton et al. Cell Reports 2015) and tissue regeneration, as shown, for example, in a first report of constructing a fully functional human tissue (cornea) from molecularly defined adult stem cells (Ksander et al. Nature 2014). As a result of these discoveries, advanced EMA- and/or FDA-approved human clinical trials are currently underway to translate ABCB5+ dermal mesenchymal stem cell (DMSC)- and ABCB5+ limbal stem cell (LSC)-based strategies to novel therapies for multiple disorders of aberrant immune activation and tissue regeneration (ClinicalTrials.gov Identifiers: NCT04971161 – chronic venous ulcer disease (CVU); NCT03549299 – limbal stem cell deficiency (LSCD); NCT03529877 – recessive dystrophic epidermolysis bullosa (RDEB)), with initial successful clinical results in cutaneous wound healing and RDEB now already available (Kerstan et al. JID Innovations 2021; Kiritsi et al. JCI Insight 2021). Additionally, Germany’s Federal Institute for Vaccines and Biomedicines (Paul-Ehrlich-Institut) recently granted national approval for allogeneic ABCB5+ DMSCs (AMESANAR®) as an Advanced Therapy Medicinal Product (ATMP) for treatment of chronic wounds in patients with chronic venous insufficiency.

Dr. Frank's laboratory has also shown that ABCB5 serves as a multidrug resistance transporter in cancer stem cells of several human malignancies, including malignant melanoma, colorectal cancer and glioblastoma, conferring resistance to chemotherapy. Specifically, his laboratory's work has shown that 1) ABCB5 marks malignant melanoma subpopulations of cancer stem cell phenotype and function that possess specific roles in the evasion of antitumor immunity and tumor-promoting vasculogenic mimicry; 2) ABCB5 correlates with cancer progression in melanoma, colorectal cancer and glioblastoma patients and serves as a prognostic marker of disease progression or recurrence; and 3) ABCB5 can be therapeutically targeted to inhibit tumor growth (Schatton et al. Nature 2008, cover article). These findings established for the first time proof-of-principle for the potential therapeutic utility of the cancer stem cell concept and hence have provided a key rationale for the development and clinical translation of cancer stem cell- targeted therapeutic strategies. Therefore, efforts are currently underway to further develop fully human high-affinity ABCB5 monoclonal antibodies as novel cancer stem cell-targeted drug candidates for clinical therapy.

Publications

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  • Kiritsi D, Dieter K, Niebergall-Roth E, Fluhr S, Daniele C, Esterlechner J, Sadeghi S, Ballikaya S, Erdinger L, Schauer F, Gewert S, Laimer M, Bauer JW, Hovnanian A, Zambruno G, El Hachem M, Bourrat E, Papanikolaou M, Petrof G, Kitzmüller S, Ebens CL, Frank MH, Frank NY, Ganss C, Martinez AE, McGrath JA, Tolar J, Kluth MA. Clinical trial of ABCB5-positive mesenchymal stem cells for recessive dystrophic epidermolysis bullosa. JCI Insight 2021. PubMed
  • Sasamoto Y, Lee CAA, Yoshihara M, Martin G, Ksander BR, Frank MH, Frank NY. High expression of SARS-CoV2 viral entry-related proteins in human limbal stem cells. Ocul Surf 2021. PubMed
  • Watanabe S, Hayashi R, Sasamoto Y, Tsujikawa M, Ksander BR, Frank MH, Quantock AJ, Frank NY, Nishida K. Human iPS cells engender corneal epithelial stem cells with holoclone-forming capabilities. iScience 2021; 24:102688. PubMed
  • Norrick A, Esterlechner J, Niebergall-Roth E, Dehio U, Sadeghi S, Schröder HM, Ballikaya S, Stemler N, Ganss C, Dieter K, Dachtler AK, Merz P, Sel S, Chodosh J, Cursiefen C, Frank NY, Auffarth GU, Ksander B, Frank MH, Kluth MA. Process development and safety evaluation of ABCB5 limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency. Stem Cell Res Ther 2021; 12:194. PubMed
  • Riedl J, Pickett-Leonard M, Eide C, Kluth MA, Ganss C, Frank NY, Frank MH, Ebens CL, Tolar J. ABCB5+ dermal mesenchymal stromal cells with favorable skin homing and local immunomodulation for Recessive Dystrophic Epidermolysis Bullosa treatment. Stem Cells 2021. PubMed
  • Frank MH, Wilson BJ, Gold JS, Frank NY. Clinical Implications of colorectal cancer stem cells in the age of single-cell OMICs and targeted therapies. Gastroenterology 2021. PubMed
  • Kerstan A, Niebergall-Roth E, Esterlechner J, Schröder HM, Gasser M, Waaga-Gasser AM, Goebeler M, Rak K, Schrüfer P, Endres S, Hagenbusch P, Kraft K, Dieter K, Ballikaya S, Stemler N, Sadeghi S, Tappenbeck N, Murphy GF, Orgill DP, Frank NY, Ganss C, Scharffetter-Kochanek K, Frank MH, Kluth MA. Ex vivo-expanded highly pure ABCB5 mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data. Cytotherapy 2021; 23:165-175. PubMed
  • Lee CAA, Banerjee P, Wilson BJ, Wu S, Guo Q, Berg G, Karpova S, Mishra A, Lian JW, Tran J, Emmerich M, Murphy GF, Frank MH, Frank NY. Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism. J Biol Chem 2020; 295:7774-7788. PubMed
  • Khattak MA, Reid A, Freeman J, Pereira M, McEvoy A, Lo J, Frank MH, Meniawy T, Didan A, Spencer I, Amanuel B, Millward M, Ziman M, Gray E. PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study. Oncologist 2020; 25:e520-e527. PubMed
  • Ballikaya S, Sadeghi S, Niebergall-Roth E, Nimtz L, Frindert J, Norrick A, Stemler N, Bauer N, Rosche Y, Kratzenberg V, Pieper J, Ficek T, Frank MH, Ganss C, Esterlechner J, Kluth MA. Process data of allogeneic ex vivo-expanded ABCB5 mesenchymal stromal cells for human use: off-the-shelf GMP-manufactured donor-independent ATMP. Stem Cell Res Ther 2021; 11:482. PubMed
  • Li F, Yuan CW, Xu S, Zu T, Woappi Y, Lee CAA, Abarzua P, Wells M, Ramsey MR, Frank NY, Wu X, Mandinova A, Frank MH, Lian CG, Murphy GF. Loss of the Epigenetic Mark, 5-hmC, in Psoriasis: Implications for Epidermal Stem Cell Dysregulation. J Invest Dermatol 2019. PubMed
  • Khattak MA, Reid A, Freeman J, Pereira M, McEvoy A, Lo J, Frank MH, Meniawy T, Didan A, Spencer I, Amanuel B, Millward M, Ziman M, Gray E. PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study. Oncologist 2019. PubMed
  • Hartwig V, Dewidar B, Lin T, Dropmann A, Ganss C, Kluth MA, Tappenbeck N, Tietze L, Christ B, Frank MH, Vogelmann R, Ebert MPA, Dooley S. Correction to: Human skin-derived ABCB5 stem cell injection improves liver disease parameters in Mdr2KO mice. Arch. Toxicol. 2021; 93:3669-3670. PubMed
  • Sasamoto Y, Sasamoto N, Tran J, Mishra A, Ksander BR, Frank MH, Frank NY. Investigation of factors associated with ABCB5-positive limbal stem cell isolation yields from human donors. Ocul Surf 2019. PubMed
  • Vander Beken S, de Vries JC, Meier-Schiesser B, Meyer P, Jiang D, Sindrilaru A, Ferreira FF, Hainzl A, Schatz S, Muschhammer J, Scheurmann NJ, Kampilafkos P, Seitz AM, Dürselen L, Ignatius A, Kluth MA, Ganss C, Wlaschek M, Singh K, Maity P, Frank NY, Frank MH, Scharffetter-Kochanek K. Newly Defined ATP-binding cassette subfamily B member 5 Positive Dermal Mesenchymal Stem Cells Promote Healing of Chronic Iron-Overload Wounds via Secretion of Interleukin-1 Receptor Antagonist. Stem Cells 2019. PubMed
  • Tappenbeck N, Schröder HM, Niebergall-Roth E, Hassinger F, Dehio U, Dieter K, Kraft K, Kerstan A, Esterlechner J, Frank NY, Scharffetter-Kochanek K, Murphy GF, Orgill DP, Beck J, Frank MH, Ganss C, Kluth MA. In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials. Cytotherapy 2019. PubMed
  • Aya-Bonilla C, Gray ES, Manikandan J, Freeman JB, Zaenker P, Reid AL, Khattak MA, Frank MH, Millward M, Ziman M. Immunomagnetic-Enriched Subpopulations of Melanoma Circulating Tumour Cells (CTCs) Exhibit Distinct Transcriptome Profiles. Cancers (Basel) 2019. PubMed
  • Hartwig V, Dewidar B, Lin T, Dropmann A, Ganss C, Kluth MA, Tappenbeck N, Tietze L, Christ B, Frank M, Vogelmann R, Ebert MPA, Dooley S. Human skin-derived ABCB5 stem cell injection improves liver disease parameters in Mdr2KO mice. Arch. Toxicol. 2020; 93:2645-2660. PubMed
  • Guo Q, Grimmig T, Gonzalez G, Giobbie-Hurder A, Berg G, Carr N, Wilson BJ, Banerjee P, Ma J, Gold JS, Nandi B, Huang Q, Waaga-Gasser AM, Lian CG, Murphy GF, Frank MH, Gasser M, Frank NY. ATP-binding cassette member B5 (ABCB5) promotes tumor cell invasiveness in human colorectal cancer. J Biol Chem 2018. PubMed
  • Gonzalez G, Sasamoto Y, Ksander BR, Frank MH, Frank NY. Limbal stem cells: identity, developmental origin, and therapeutic potential. Wiley Interdiscip Rev Dev Biol 2017. PubMed
  • Webber BR, O'Connor KT, McElmurry RT, Durgin EN, Eide CR, Lees CJ, Riddle MJ, Mathews WE, Frank NY, Kluth MA, Ganss C, Moriarity BS, Frank MH, Osborn MJ, Tolar J. Rapid generation of Col7a1(-/-) mouse model of recessive dystrophic epidermolysis bullosa and partial rescue via immunosuppressive dermal mesenchymal stem cells. Lab Invest 2017; 97:1218-1224. PubMed
  • Borchers S, Maβlo C, Müller CA, Tahedl A, Volkind J, Nowak Y, Umansky V, Esterlechner J, Frank MH, Ganss C, Kluth MA, Utikal J. Detection of ABCB5 tumour antigen-specific CD8(+) T cells in melanoma patients and implications for immunotherapy. Clin Exp Immunol 2017. PubMed
  • Aya-Bonilla CA, Marsavela G, Freeman JB, Lomma C, Frank MH, Khattak MA, Meniawy TM, Millward M, Warkiani ME, Gray ES, Ziman M. Isolation and detection of circulating tumour cells from metastatic melanoma patients using a slanted spiral microfluidic device. 2017; 8:67355-67368. PubMed
  • Gasser M, Kim M, Rehder R, Frank N, Frank M, Grimmig T, Moench R, Ribas C, Illert B, Germer CT, Rosenwald A, Waaga-Gasser AM. Clinical Significance of Disseminated Pluripotent Tumor Cell Signature Expression in the Bone Marrow from Patients with Colorectal Cancer. J Cancer Sci Ther 2021; 9:669-674. PubMed
  • Jiang D, Muschhammer J, Qi Y, Kügler A, de Vries JC, Saffarzadeh M, Sindrilaru A, Beken SV, Wlaschek M, Kluth MA, Ganss C, Frank NY, Frank MH, Preissner KT, Scharffetter-Kochanek K. Suppression of Neutrophil-Mediated Tissue Damage-A Novel Skill of Mesenchymal Stem Cells. Stem Cells 2016. PubMed
  • Kleffel S, Lee N, Lezcano C, Wilson BJ, Sobolewski K, Saab KR, Mueller H, Zhan Q, Posch C, Elco CP, DoRosario A, Garcia SS, Thakuria M, Wang YE, Wang LC, Murphy GF, Frank MH, Schatton T. ABCB5-targeted chemoresistance reversal inhibits Merkel cell carcinoma growth. J Invest Dermatol 2016. PubMed
  • Schatton T, Schütte U, Frank MH. Effects of Malignant Melanoma Initiating Cells on T-Cell Activation. Methods Mol Biol 2016. PubMed
  • Lutz NW, Banerjee P, Wilson BJ, Ma J, Cozzone PJ, Frank MH. Expression of Cell-Surface Marker ABCB5 Causes Characteristic Modifications of Glucose, Amino Acid and Phospholipid Metabolism in the G3361 Melanoma-Initiating Cell Line. PLoS ONE 2016; 11:e0161803. PubMed
  • Ma J, Frank MH. Isolation of Circulating Melanoma Cells. Methods Mol Biol 2015. PubMed
  • Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, Elco CP, Lee N, Juneja VR, Zhan Q, Lian CG, Thomi R, Hoetzenecker W, Cozzio A, Dummer R, Mihm MC, Flaherty KT, Frank MH, Murphy GF, Sharpe AH, Kupper TS, Schatton T. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell 2015; 162:1242-56. PubMed
  • Schatton T, Yang J, Kleffel S, Uehara M, Barthel SR, Schlapbach C, Zhan Q, Dudeney S, Mueller H, Lee N, de Vries JC, Meier B, Vander Beken S, Kluth MA, Ganss C, Sharpe AH, Waaga-Gasser AM, Sayegh MH, Abdi R, Scharffetter-Kochanek K, Murphy GF, Kupper TS, Frank NY, Frank MH. ABCB5 Identifies Immunoregulatory Dermal Cells. Cell Rep 2015. PubMed
  • Gray ES, Reid AL, Bowyer S, Calapre L, Siew K, Pearce R, Cowell L, Frank MH, Millward M, Ziman M. Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment. J Invest Dermatol 2015. PubMed
  • de Waard NE, Kolovou PE, McGuire SP, Cao J, Frank NY, Frank MH, Jager MJ, Ksander BR. Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma. Ocul Oncol Pathol 2015; 1:182-189. PubMed
  • Frank MH, Frank NY. Restoring the cornea from limbal stem cells. Regen Med 2015; 10:1-4. PubMed
  • Lee CW, Zhan Q, Lezcano C, Frank MH, Huang J, Larson AR, Lin JY, Wan MT, Lin PI, Ma J, Kleffel S, Schatton T, Lian CG, Murphy GF. Nestin depletion induces melanoma matrix metalloproteinases and invasion. Lab Invest 2014. PubMed
  • Murphy GF, Wilson BJ, Girouard SD, Frank NY, Frank MH. Stem cells and targeted approaches to melanoma cure. Mol Aspects Med 2014. PubMed
  • Wilson BJ, Saab KR, Ma J, Schatton T, Pütz P, Zhan Q, Murphy GF, Gasser M, Waaga-Gasser AM, Frank NY, Frank MH. ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit. Cancer Res 2014; 74:4196-207. PubMed
  • Ksander BR, Kolovou PE, Wilson BJ, Saab KR, Guo Q, Ma J, McGuire SP, Gregory MS, Vincent WJ, Perez VL, Cruz-Guilloty F, Kao WW, Call MK, Tucker BA, Zhan Q, Murphy GF, Lathrop KL, Alt C, Mortensen LJ, Lin CP, Zieske JD, Frank MH, Frank NY. ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature 2014; 511:353-7. PubMed
  • Volpicelli ER, Lezcano C, Zhan Q, Girouard SD, Kindelberger DW, Frank MH, Frank NY, Crum CP, Murphy GF. The multidrug-resistance transporter ABCB5 is expressed in human placenta. Int J Gynecol Pathol 2013; 33:45-51. PubMed
  • Lin JY, Zhang M, Schatton T, Wilson BJ, Alloo A, Ma J, Qureshi AA, Frank NY, Han J, Frank MH. Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk. Biochem Biophys Res Commun 2013. PubMed
  • Nedosekin DA, Sarimollaoglu M, Galanzha EI, Sawant R, Torchilin VP, Verkhusha VV, Ma J, Frank MH, Biris AS, Zharov VP. Synergy of photoacoustic and fluorescence flow cytometry of circulating cells with negative and positive contrasts. J Biophotonics 2013; 6:425-34. PubMed
  • Reid AL, Millward M, Pearce R, Lee M, Frank MH, Ireland A, Monshizadeh L, Rai T, Heenan P, Medic S, Kumarasinghe P, Ziman M. Markers of circulating tumour cells in the peripheral blood of patients with melanoma correlate with disease recurrence and progression. Br J Dermatol 2013; 168:85-92. PubMed
  • Cedeno-Laurent F, Opperman MJ, Barthel SR, Hays D, Schatton T, Zhan Q, He X, Matta KL, Supko JG, Frank MH, Murphy GF, Dimitroff CJ. Metabolic inhibition of galectin-1-binding carbohydrates accentuates antitumor immunity. J Invest Dermatol 2012. PubMed
  • Wilson BJ, Schatton T, Zhan Q, Gasser M, Ma J, Saab KR, Schanche R, Waaga-Gasser AM, Gold JS, Huang Q, Murphy GF, Frank MH, Frank NY. ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients. Cancer Res 2011. PubMed
  • Wilson BJ, Schatton T, Frank MH, Frank NY. Colorectal Cancer Stem Cells: Biology and Therapeutic Implications. 2011; 7:128-135. PubMed
  • Ho J, Pandey P, Schatton T, Sims-Lucas S, Khalid M, Frank MH, Hartwig S, Kreidberg JA. The pro-apoptotic protein Bim is a microRNA target in kidney progenitors. J Am Soc Nephrol 2011; 22:1053-63. PubMed
  • Laga AC, Zhan Q, Weishaupt C, Ma J, Frank MH, Murphy GF. SOX2 and nestin expression in human melanoma: an immunohistochemical and experimental study. Exp Dermatol 2011; 20:339-45. PubMed
  • Frank NY, Schatton T, Kim S, Zhan Q, Wilson BJ, Ma J, Saab KR, Osherov V, Widlund HR, Gasser M, Waaga-Gasser AM, Kupper TS, Murphy GF, Frank MH. VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth. Cancer Res 2011. PubMed
  • Ma J, Lin JY, Alloo A, Wilson BJ, Schatton T, Zhan Q, Murphy GF, Waaga-Gasser AM, Gasser M, Hodi FS, Frank NY, Frank MH. Isolation of tumorigenic circulating melanoma cells. Biochem Biophys Res Commun 2010; 402:711-7. PubMed
  • Schatton T, Frank MH. The in vitro spheroid melanoma cell culture assay: cues on tumor initiation? J Invest Dermatol 2010; 130:1769-71. PubMed
  • Izawa A, Schatton T, Frank NY, Ueno T, Yamaura K, Pendse SS, Margaryan A, Grimm M, Gasser M, Waaga-Gasser AM, Sayegh MH, Frank MH. A novel in vivo regulatory role of P-glycoprotein in alloimmunity. Biochem Biophys Res Commun 2010; 394:646-52. PubMed
  • Ma J, Frank MH. Tumor initiation in human malignant melanoma and potential cancer therapies. Anticancer Agents Med Chem 2010; 10:131-6. PubMed
  • Schatton T, Schütte U, Frank NY, Zhan Q, Hoerning A, Robles SC, Zhou J, Hodi FS, Spagnoli GC, Murphy GF, Frank MH. Modulation of T-Cell Activation by Malignant Melanoma Initiating Cells. Cancer Res 2010; 70:697-708. PubMed
  • Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. J Clin Invest 2010; 120:41-50. PubMed
  • Schatton T, Frank NY, Frank MH. Identification and targeting of cancer stem cells. Bioessays 2009; 31:1038-49. PubMed
  • Frank NY,Frank MH. ABCB5 gene amplification in human leukemia cells. Leuk Res 2009; 33:1303-5. PubMed
  • Schatton T, Frank MH. Antitumor immunity and cancer stem cells. Ann N Y Acad Sci 2009; 1176:154-69. PubMed
  • Behjati S, Frank MH. The effects of tamoxifen on immunity. Curr Med Chem 2009; 16:3076-80. PubMed
  • Schatton T, Frank MH. Cancer stem cells and human malignant melanoma. Pigment Cell Melanoma Res 2008; 21:39-55. PubMed
  • Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH. Identification of cells initiating human melanomas. Nature 2008; 451:345-9. PubMed
  • Pendse SS, Behjati S, Schatton T, Izawa A, Sayegh MH, Frank MH. P-glycoprotein functions as a differentiation switch in antigen presenting cell maturation. Am J Transplant 2006; 6:2884-93. PubMed
  • Frank NY, Kho AT, Schatton T, Murphy GF, Molloy MJ, Zhan Q, Ramoni MF, Frank MH, Kohane IS, Gussoni E. Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin. J Cell Biol 2006; 175:99-110. PubMed
  • Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM, Gasser M, Sayegh MH, Sadee W, Frank MH. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 2005; 65:4320-33. PubMed
  • Frank NY, Pendse SS, Lapchak PH, Margaryan A, Shlain D, Doeing C, Sayegh MH, Frank MH. Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem 2003; 278:47156-65. PubMed
  • Pendse SS, Briscoe DM, Frank MH. P-glycoprotein and alloimmune T-cell activation. 2011; 4:3-14. PubMed
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