WO2016134463A1 - Peptide s1009a pour le traitement des leucémies - Google Patents

Peptide s1009a pour le traitement des leucémies Download PDF

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Publication number
WO2016134463A1
WO2016134463A1 PCT/CA2016/050177 CA2016050177W WO2016134463A1 WO 2016134463 A1 WO2016134463 A1 WO 2016134463A1 CA 2016050177 W CA2016050177 W CA 2016050177W WO 2016134463 A1 WO2016134463 A1 WO 2016134463A1
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peptide
composition
peptidomimetic
cells
seq
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PCT/CA2016/050177
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English (en)
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Philippe Tessier
Frédéric BARABÉ
Malika LAOUEDJ
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UNIVERSITé LAVAL
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1738—Calcium binding proteins, e.g. calmodulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present description relates to a composition comprising S100A9 peptide for treating leukemias.
  • Acute leukemias are the result of a series of genetic and epigenetic events occurring in a stem or progenitor hematopoietic cell, giving rise to a clonal expansion of progenitors with an impaired capacity to differentiate.
  • the past 20 years have been very fruitful in the identification of recurrent genetic lesions in acute leukemias. Improvement in leukemia-free survival has been mostly due to better risk stratification which allows for adjustment of treatment intensity and also to allogenic hematopoietic stem cell transplantation.
  • drugs used in acute myeloid treatment (AML) are basically the same today as they were 25-30 years ago and prognosis remains poor.
  • the 5-year survival rate is as low as 55% for children with AML and even worse for adults (30-40%) and elderly (> 65 yo) ( ⁇ 15%). Therefore, novel and innovative approaches need to be explored in order to improve leukemia-free survival of acute leukemia patients.
  • composition comprising S100A9 peptide or a peptidomimetic thereof, and a carrier for treating leukemia.
  • S100A9 peptide is human S100A9 protein.
  • the peptide comprises the amino acid sequence set forth in SEQ ID NO: 1 .
  • the peptide has at least 60%, at least 70% or at least 80%, at least 90% identical, or at least about 95% identity with SEQ ID NO: 1 .
  • the peptide consists of the amino acid sequence set forth in SEQ ID NO: 1 .
  • the peptide of or the peptidomimetic thereof comprises a chemically or enzymatically attached modification.
  • the peptide or peptidomimetic thereof is pegylated, hesylated, pasylated, myristoylated, or glycosylated.
  • composition described herein is formulated for an oral administration, an inhalation, a nasal administration, or an administration by injection.
  • the injection is subcutaneously.
  • composition described herein further comprises a chemotherapeutic agent.
  • the chemotherapeutic agent is an alkylating/alkaloid agent, an antimetabolite, a hormone, a hormone analog, or an antineoplastic drug.
  • the chemotherapeutic agent is cytarabine (cytosine arabinoside, Ara-C, Cytosar-U), carboplatin, carmustine, chlorambucil, dacarbazine, ifosfamide, lomustine, mechlorethamine, procarbazine, pentostatin, (2'deoxycoformycin), etoposide, teniposide, topotecan, vinblastine, vincristine, paclitaxel, dexamethasone, methylprednisolone, prednisone, all-trans retinoic acid, arsenic trioxide, interferon-alpha, rituximab (Rituxan®), gemtuzumab ozogamicin, imatinib mesylate, melphalan, busulfan (Myleran®), thiotepa, bleomycin, platinum (cisplatin), cyclopho
  • a method of treating leukemia in the subject comprising administering to said subject an effective amount of the S100A9 peptide or peptidomimetic thereof, of the composition described herein.
  • the subject is a mouse or a human.
  • Fig. 1 illustrates the secretion of S100A8/A9 in the serum of mice with primary leukemias, the primary leukemia generated by injecting mouse hematopoietic stem/progenitor cells transfected with a retrovirus expressing GFP, as well as genes HOXA9 and MEIS1 (3 different primary mice: AH13, AH 15 and AH 16), wherein peripheral blood was harvested from moribund or control mice, and the S100A8/A9 concentrations were measured by ELISA in serum, wherein the data are the mean ⁇ sem of 3 independent measurements.
  • Fig. 2 illustrates the S100A9 protection of mice injected with HoxA9- MEIS1 leukemia.
  • Fig. 3 illustrates the S100A9 treatment increase of latency of HOXA9-MEIS1 leukemia in secondary mice.
  • Fig. 4A illustrates a photographic depiction of the increased differentiation of AML cells in mice treated with S100A9.
  • Fig. 4B illustrates the increased differentiation of AML cells in bone marrow and blood (neutro, band cells, metamyelocytes, myelocytes, blast) in mice treated with S100A9.
  • Fig. 5 illustrates that S100A9 promotes the growth arrest of mouse leukemia cells.
  • Fig. 6 illustrates that S100A9 promotes the differentiation of human leukemia cells.
  • Fig. 7 illustrates that S100A9 induces differentiation of human AML cells of human patients.
  • Fig. 8A illustrates that S100A9 induces differentiation of human AML cells of a human patient by measuring the differentiation marker CD14.
  • Fig. 8B illustrates that S100A9 induces differentiation of human AML cells of a human patient by examining the cell cycle by propidium, iodide staining.
  • Fig. 9A illustrates that S100A9 promote differentiation of the AML cell line Mono-Mac-1 by measuring the expression of the differentiation marker CD14.
  • Fig. 9B illustrates that S100A9 promote growth arrests of the AML cell line Mono-Mac-1 by measuring the number of cells.
  • composition comprising a peptide comprising the amino acid sequence set forth in SEQ ID NO: 1 and a carrier for treating leukemia.
  • composition comprising S100A9 peptide for treating leukemias, more particularly acute leukemias.
  • the S100 protein family comprises 22 members of small (10 to 14 kDa) acidic calcium-binding proteins named as S100A1 , S100A2, and so on, according to the time of their discovery and on the chromosome on which they are found. These intracellular proteins are involved in the control of protein phosphorylation, enzymatic activities, Ca 2+ homeostasis, and intermediate filaments polymerisation. S100A8, S100A9 and S100A12 belong to a subset called myeloid related proteins (MRPs) because they are predominantly expressed in neutrophils (30% of cytoplasmic protein) and monocytes, which derive from myeloid precursors.
  • MRPs myeloid related proteins
  • S100A9 also known as calgranulin B and myeloid related protein-14 (MRP-14), is a calcium- and zinc-binding protein that belongs to the S100 protein family. S100A9 is highly expressed by the myeloid cell lineage and is found in the extracellular milieu during inflammatory conditions. S100A9 forms heterodimers with S100A8, another member of the S100 family. However, S100A9 may also form monomers which execute specific functions. Human S100A9 has a molecular mass of about 13 kDa and is composed of 1 14 amino acid residues.
  • S100A9 is expressed abundantly in neutrophils and monocytes. Epithelial, mesenchymal and endothelial cells can also express and secrete S100A9 under infectious or inflammatory conditions. S100A8 and S100A9 are arranged as noncovalently bonded homodimers. In addition, in the presence of calcium, S100A8 and S100A9 form a noncovalent heterodimer called S100A8/A9 or calprotectin, presumed to be involved in the cellular control of calcium concentrations.
  • S100A9 promotes inflammation by enhancing phagocyte migration and inducing the secretion of pro-inflammatory cytokines, as well as the release of tissue-degrading enzymes and ROS. These activities are presumably counterbalanced by oxidized S100A8 which acts as an anti-inflammatory factor.
  • S100A8 and S100A9 are presumed to bind to RAGE, the scavenger receptor (CD36), CD33 or the Toll-like receptor 4 (TLR4).
  • Potential receptors for S100A8 and S100A9 on the surface of leukemic cells have never been investigated although TCGA data show TLR2, TLR4 and CD36, but not RAGE, are expressed at high levels (average RPKM values > 20) in AML patient samples. These receptors are also highly expressed on normal cells (monocytes, granulocytes), while S100A8 and S100A9 knockout mice seem to have normal hematopoiesis. These data suggest that targeting the S100A8/A9 complex is a better strategy than targeting the receptors to maximize the therapeutic effects and minimize the side effects on normal blood cell populations.
  • U.S. patents nos. 7,553,488 and 8,282,925 disclose the use of an inhibitor or antagonist of S100A9, such as an antibody, for modulating, reducing or treating inflammation.
  • U.S. patent application no. 62/191 ,733 describes the use of a humanized anti-S100A9 antibody for reducing or inhibiting inflammation.
  • European patent no. 1608397 describes the use of a composition comprising S100A9 protein for stimulating proliferation, differentiation and release of neutrophils in a patient.
  • TCGA Cancer Genome Atlas
  • S100A8 and S100A9 were amongst the top 5 discriminatory genes for one important sub-group mainly composed of myelomonocytic and monocytic AML, with high RPKM levels (Cancer Genome Atlas Research, N., 2013, The New England journal of medicine, 368: 2059-2074).
  • S100A8 and S100A9 proteins are found in the serum of patients with acute and chronic myeloid leukemia (Ivanov et al., 1996, Immunology letters, 49: 7-13) (AML and CML, Fig 1 ), and these concentrations correlate with growth-stimulating activity in these sera (Fig 2).
  • S100A8 has been identified as a predictor of poor survival in de novo AML patients (Nicolas et al., 201 1 , Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 25: 57-65).
  • S100A8/A9 constitutive over-expression of S100A8/A9 is also associated with resistance to prednisone treatment in MLL-rearranged B-ALL, and forced expression of S100A8/A9 in MLL-rearranged B-ALL cells transform prednisone-sensitive into prednisone insensitive cells in vitro (Spijkers-Hagelstein et al., 2012, Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 26: 1255-1265. Taken together, these data confirm the expression of S100A8/A9 in acute leukemias.
  • composition comprising a peptide comprising the amino acid sequence set forth in SEQ ID NO: 1 for treating leukemia.
  • peptide is used broadly to mean peptides, proteins, fragments of proteins and the like.
  • the peptide disclosed herein may be synthesized as a peptide mimetic, mimicking the biological activity of the native peptide.
  • Aslo encompassed is a peptidomimetic, meaning a peptide-like molecule that has the activity of the native peptide.
  • Such peptidomimetic include a chemically-modified peptide, and a peptide-like molecule containing non- naturally occurring amino acids.
  • a peptidomimetic can include amino acid analogs and can be a peptide-like molecule which contains, for example, an amide bond isostere such as a retro-inverso modification; reduced amide bond; methylenethioether or methylenesulfoxide bond; methylene ether bond; ethylene bond; thioamide bond; trans-olefm or fluoroolefin bond; 1 ,5- disubstituted tetrazole ring; ketomethylene or fluoroketomethylene bond or another amide isostere.
  • a peptide comprising the amino acid sequence set forth in SEQ ID NO: 1 , or a conservative substitute or a peptidomimetic thereof.
  • the peptide consists of the amino acid sequence set forth in SEQ ID NO: 1 , or a conservative substitute or peptidomimetic of the sequence.
  • a "conservative substitute” is an amino acid sequence in which a first amino acid is replaced by a second amino acid or amino acid analog having at least one similar biochemical property, which can be, for example, similar size, charge, hydrophobicity or hydrogen-bonding capacity.
  • a first hydrophobic amino acid alanine can be conservatively substituted with a second (non-identical) hydrophobic amino acid such as alanine (Ala), valine (Val), leucine (Leu), or isoleucine (He), or an analog thereof.
  • a first amino acid having an uncharged side chain i.e., serine, threonine and glutamine
  • a second (non-identical) amino acid such as serine (Ser), threonine (Thr), asparagine (Asn) and glutamine (Gin), or an analog thereof.
  • the peptide used in the compositions and methods described herein consists essentially of a peptide which is at least 60%, at least 70% or at least 80% identical to SEQ ID NO: 1 . In another embodiment, the peptide is at least 90% identical to SEQ ID NO: 1 . In another embodiment, the peptide is at least about 95% identical to SEQ ID NO: 1 .
  • modified forms of the peptide and peptidomimetic described herein may comprise e.g. chemically or enzymatically attached modifications that render the peptide more stable, e.g. against protease degradation, that allow to provide the peptides or peptidomimetic as pharmaceutically acceptable salts, or which e.g. improve the biological properties of the peptide or peptidomimetic such as half-life.
  • such modifications include pegylated, hesylated, pasylated, myristoylated, glycosylated, and/or cyclic forms of the peptide and/or peptidomimetic, and in particular the peptide of SEQ ID NO: 1 or a peptidomimetic of this sequence.
  • the peptide, peptidomimetic and/or composition described herein is formulated for oral administration, inhalation, nasal administration, or for an administration by injection such as subcutaneously.
  • the peptide described herein is used in combination with a chemotherapeutic agent.
  • a chemotherapeutic agent with therapeutic usefulness in the treatment of leukemias known in the art.
  • Chemotherapeutic agents as used herein encompass both chemical and biological agents. Categories of chemotherapeutic agents include alkylating/alkaloid agents, antimetabolites, hormones or hormone analogs, and miscellaneous antineoplastic drugs.
  • the chemotherapeutic agent encompassed herein is cytarabine (cytosine arabinoside, Ara-C, Cytosar-U), carboplatin, carmustine, chlorambucil, dacarbazine, ifosfamide, lomustine, mechlorethamine, procarbazine, pentostatin, (2'deoxycoformycin), etoposide, teniposide, topotecan, vinblastine, vincristine, paclitaxel, dexamethasone, methylprednisolone, prednisone, all-trans retinoic acid, arsenic trioxide, interferon-alpha, rituximab (Rituxan®), gemtuzumab ozogamicin, imatinib mesylate, melphalan, busulfan (Myleran®), thiotepa, bleomycin, platinum (cisplatin),
  • S100A8/A9 concentrations are increased in the serum of patients with AML and CML (Fig. 1 ), correlate with growth activity (Fig. 2) and blocking S100A8/A9 inhibits the proliferation of AML cells (Fig. 3).
  • S100A8/A9 was reported to induce apoptosis in various tumor cell lines (Yui et al., 1997, Journal of leukocyte biology, 61 : 50-57), but this effect has not been validated in vivo.
  • This heterodimer also binds to and activates NF- ⁇ , and induces proliferation of colonic and prostate tumor cell lines (Hermani et al., 2006, Experimental cell research, 312: 184-197).
  • lymphoma and sarcoma growth is reduced in S100a9 'A mice due to a reduction of myeloid- derived suppressor cell numbers and activity (Cheng et al., 2008, The Journal of experimental medicine, 205: 2235-2249).
  • S100A8/A9 expression by lung phagocytes has also been linked to metastasis and migration to this organ (Hiratsuka et al., 2006, Nature cell biology, 8: 1369-1375).
  • murine hematopoietic stem/progenitor cells were transduced using retroviral vectors to express HOXA9-MEIS1 and injected into irradiated mice.
  • HOXA9-MEIS1 expressing cells generated AML at a median of 60 days after transplantation with the same phenotype.
  • An important increase of S100A8/A9 in the serum of the model leukemia was observed (Fig. 1 ), demonstrating that this model recapitulates the increase in S100A8/A9 concentration in the serum seen in patients.
  • S100A8 and S100A9 were only expressed, but at high levels, in a fraction of leukemic cells (approximately 10%) in the bone marrow and may correspond to leukemic fraction with higher leukemia stem cell frequency as these cells also express levels of Ly6G and c-kit, 2 genes overexpressed in leukemia stem cells.
  • HOXA9-MEIS1 leukemic cells from murine bone marrow of primary recipients were collected and then injected into secondary mice. This strategy allows for a shorter and homogeneous latency in multiple mice using the same clonal disease.
  • the therapeutic effect of recombinant S100A9 protein was tested on HOXA9-MEIS1 leukemia in vivo. Mice were intra-peritoneally (i.p.) injected with S100A9 (20 ⁇ g/mouse) 3 times a week, starting on day 3 post- injection of leukemia cells. Treatment with S100A9 protein reduced weight loss associated with leukemia (Fig. 2), suggesting that S100A9 protein, reduces the proliferation of leukemia cells.
  • S100A9 protein The effect of S100A9 protein on the survival of mice with secondary HOXA9/MEIS1 leukemia was tested, using S100A8 protein as a control. Injection of S100A8 had no effect on the survival of mice with AML. 100,000 bone marrow cells from a HOXA9-MEIS1 primary leukemic mouse were injected in sub-lethally irradiated secondary mice, and recombinant S100A8 or S100A9 (20 ⁇ g/mouse) were injected 3 times a week from day 3 till day 35 (6 mice per group) (** p ⁇ 0.01 , t-test) (Fig. 3). Injections of S100A9 prolonged survival of mice with AML (Fig. 3).
  • mice did not show any sign of leukemia at day 60 post-injection of leukemia cells, demonstrating that injection of S100A9 is sufficient to cure from leukemia.
  • Histological analyses showed increased differentiation of leukemia cells in the bone marrow and blood of mice injected with S100A9 protein (Fig. 4A and B), demonstrating that injection of S100A9 promotes the differentiation of leukemia cells.
  • 100,000 bone marrow cells from a HOXA9-MEIS1 primary leukemic mouse were injected in sub-lethally irradiated C57BL/6 mice.
  • Recombinant S100A9 (20 ⁇ g/mouse) was injected 3 times a week from day 15 till day 35 (6 mice per group), wherein Wright-Giemsa staining of cytosins of bone marrow or blood cells at the time of sacrifice (>80% cells GFP+) showed increased differentiation of cells (Fig. 4A).
  • S100A9 The effect of S100A9 on AML cell proliferation was measured.
  • Murine HOXA9/MEIS1 leukemia cells were grown in presence or absence of murine S100A8 and S100A9 for 24h. Cell cycle was then examined by staining with propidium iodide. S100A8 protein did not affect the cell cycle of AML cells. In contrast, more cells in the G0/G1 phases were detected following stimulation with recombinant S100A9, demonstrating that S100A9 inhibits cell proliferation. Accordingly, S100A9 promotes the growth arrest of mouse leukemia cell (Fig. 5).
  • bone marrow cells from 5 M4 and M5 AML patients (03H031 , 06H061 , 07H006, 07H072, 07H138) were thawed, then cultured with 20 ⁇ g opf S100A9 for 24 hours.
  • Expression of the differentiation markers CD1 1 b and CD14 was examined by FACS. As seen in Fig. 7, S100A9 induces differentiation of human AML cells.
  • S100A9 induces differentiation and growth arrests of human AML cells (see Fig. 8A and B). Bone marrow cells from an AML patient were grown for 5 days. The cells were stimulated with 20 ⁇ g/ml of human S100A9. Expression of the differentiation marker CD14 was examined by FACS (Fig. 8A). Cell cycle was examined by propidium iodide staining (Fig. 8B).
  • S100A9 promote differentiation of the AML cell line Mono-Mac-1 , a cell line derived from the peripheral blood of a 65 year old patient with AML.
  • Mono-Mac-1 (200,000 cells per well) were grown for 3 days. The cells were stimulated with 20 ⁇ g/ml of human S100A9. Expression of the differentiation marker CD14 was examined by FACS (Fig. 9A). The cells were counted at the end of the experiment (Fig. 9B).
  • Secondary leukemia was induced by injecting 2 x 10 5 bone marrow cells from primary leukemia mice into sublethally irradiated (4Gy) recipient.
  • Human cord blood cells transfected with the fusion gene MLL-AF4 were cultivated in I MDM supplemented with 15% fetal calf serum, IL-6 and stem cell factor. The cells were plated 96 well microtiter plates (200 000 cells/well), then stimulated with 20 ⁇ g/ml of recombinant human S100A8 or S100A9, or PBS. After 72h, cells were collected and immunophenotyping was performed by flow cytometry following staining with anti- CD14.
  • Leukemia cells from peripheral blood of 5 M4 and M5 AML patients were thawed, then cultured with 20 ⁇ g of S100A9 for up to 5 days.
  • Expression of the differentiation markers CD1 1 b and CD14 was examined by FACS.
  • Cell cycle was examined by flow cytometry following propidium iodide staining.
  • Mono-Mac-1 (200,000 cells) were cultured with 20 ⁇ g of S100A9 for 3 days. The cells were then counted and expression of CD14 was analyzed by flow cytometry.

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Abstract

La présente invention concerne une composition comprenant un peptide S100A9 ou un composé peptidomimétique de celui-ci, et un support pour le traitement de la leucémie.
PCT/CA2016/050177 2015-02-25 2016-02-23 Peptide s1009a pour le traitement des leucémies WO2016134463A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084928A1 (fr) * 2003-03-28 2004-10-07 UNIVERSITé LAVAL Proteine s100 utilisee en tant qu'activateur des neutrophiles pour attenuer la neutropenie dans le traitement du cancer
WO2006005186A1 (fr) * 2004-07-13 2006-01-19 UNIVERSITé LAVAL Inhibiteurs de la proteine s100 utilises pour le traitement la leucemie
US20090305985A1 (en) * 2003-04-04 2009-12-10 The Regents Of The University Of California Immunomodulatory Agents For Treatment of Inflammatory Diseases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084928A1 (fr) * 2003-03-28 2004-10-07 UNIVERSITé LAVAL Proteine s100 utilisee en tant qu'activateur des neutrophiles pour attenuer la neutropenie dans le traitement du cancer
US20090305985A1 (en) * 2003-04-04 2009-12-10 The Regents Of The University Of California Immunomodulatory Agents For Treatment of Inflammatory Diseases
WO2006005186A1 (fr) * 2004-07-13 2006-01-19 UNIVERSITé LAVAL Inhibiteurs de la proteine s100 utilises pour le traitement la leucemie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BARABE, F. ET AL.: "Myeloid-Related Protein S 100A9 induces cellular differentiation in Acute Myeloid Leukemia through TLR2 and TLR4 receptors;", 57TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY, December 2015 (2015-12-01), Orlando, Florida, Retrieved from the Internet <URL:https://ash.confex.com/ash/2015/webprogram/Paper86520.html> *

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