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Doan, Phuong Linh

Positions:

Assistant Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

M.D. 2003

M.D. — University of North Carolina at Chapel Hill

Resident, Internal Medicine

University of North Carolina at Chapel Hill School of Medicine

Chief Medical Resident

University of North Carolina at Chapel Hill School of Medicine

Fellowship, Hematology, Oncology, Cellular Therpay

Duke University School of Medicine

Grants:

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2021

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2021

Role of ErbB Receptor Signaling in Regulating Normal and Leukemic Stem Cell Fate

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 09, 2014
End Date
August 31, 2019

Endothelial Cell-Derived Extracellular Vesicles Mitigate Hematopoietic Injury Following Ionizing Radiation

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
Columbia University
Role
Principal Investigator
Start Date
August 01, 2017
End Date
July 31, 2019

Epidermal Growth Factor Regulates Leukemic Stem Cell Self-Renewal

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
American Association for Cancer Research
Role
Principal Investigator
Start Date
July 01, 2014
End Date
June 30, 2016

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Research Candidate
Start Date
September 29, 2009
End Date
July 31, 2015
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Awards:

Duke Physician-Scientist Strong Start Award. Duke School of Medicine.

Type
School
Awarded By
DUke School of Medicine
Date
April 01, 2017

MEDx Biomedical Research Award. Duke School of Medicine and School of Engineering.

Type
School
Awarded By
Duke School of Medicine and School of Engineering
Date
April 01, 2017

Publications:

CCR5 Signaling Promotes Murine and Human Hematopoietic Regeneration following Ionizing Radiation.

Hematopoietic stem and progenitor cells (HSPCs) depend on regulatory cytokines from the marrow microenvironment. From an unbiased cytokine screen of murine marrow supernatants, we identified C-C motif chemokine ligand 5 (CCL5) as an endothelial cell-secreted hematopoietic growth factor. Following treatment with CCL5, hematopoietic regeneration is accelerated and survival is prolonged after radiation. In mice with deletion of Ccr5, hematopoietic regeneration is delayed compared to control mice. Deletion of Ccr5 specifically in hematopoietic cells was sufficient to delay regeneration, while the deletion of Ccr5 in stromal/endothelial cells was not. Mechanistically, CCL5 promotes hematopoietic cell cycling and cell survival. Like murine hematopoietic cells, human hematopoietic cells (cord blood, healthy marrow, and peripheral blood) increase CCR5 expression after radiation exposure to promote cell survival. These data establish that CCL5 and CCR5 signaling play critical roles in hematopoietic regeneration and could serve as therapeutic targets to shorten the duration of myelosuppression.

Authors
Piryani, SO; Kam, AYF; Vu, UT; Chao, NJ; Doan, PL
MLA Citation
Piryani, Sadhna O., et al. “CCR5 Signaling Promotes Murine and Human Hematopoietic Regeneration following Ionizing Radiation..” Stem Cell Reports, vol. 13, no. 1, July 2019, pp. 76–90. Pubmed, doi:10.1016/j.stemcr.2019.04.023.
PMID
31155503
Source
pubmed
Published In
Stem Cell Reports
Volume
13
Issue
1
Publish Date
2019
Start Page
76
End Page
90
DOI
10.1016/j.stemcr.2019.04.023

Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome.

PURPOSE: Myelodysplastic syndrome (MDS) is associated with a dysregulated innate immune system. The purpose of this study was to determine whether modulation of the innate immune system via high mobility group box-1 (HMGB1) could reduce cell viability in MDS. EXPERIMENTAL DESIGN: We quantified HMGB1 in an MDS cell line MDS-L and in primary MDS cells compared with nonmalignant hematopoietic cells. We performed loss-of-function studies of HMGB1 using pooled siRNAs and a small-molecule inhibitor sivelestat compared with standard chemotherapy. We measured levels of engraftment of MDS-L cells in NOD-scidIL2Rgnull (NSG) mice following treatment with sivelestat. Mechanistically, we interrogated cell survival pathways and 45 targets within the NFκB pathway using both protein analysis and a proteome profiler array. RESULTS: We discovered that HMGB1 had increased expression in both MDS-L cells and in primary CD34+ MDS cells compared with healthy CD34+ hematopoietic cells. Sivelestat impaired MDS cell expansion, increased cellular death, and spared healthy hematopoietic cells. MDS-L marrow engraftment is reduced significantly at 17 weeks following treatment with sivelestat compared with control mice. Treatment of CD34+ MDS cells with sivelestat and azacitidine or decitabine was additive to increase apoptotic cell death compared with chemotherapy alone. Sivelestat promoted apoptosis with increased expression of PUMA, activated caspase 3, and increased DNA double-strand breaks. Inhibition of HMGB1 reduced levels of Toll-like receptors (TLR) and suppressed activation of NFκB in MDS-L cells. CONCLUSIONS: Inhibition of HMGB1 could promote MDS cell death and alter innate immune responses via suppression of NFκB pathways.

Authors
Kam, AYF; Piryani, SO; McCall, CM; Park, HS; Rizzieri, DA; Doan, PL
MLA Citation
Kam, Angel Y. F., et al. “Targeting High Mobility Group Box-1 (HMGB1) Promotes Cell Death in Myelodysplastic Syndrome..” Clin Cancer Res, vol. 25, no. 13, July 2019, pp. 4155–67. Pubmed, doi:10.1158/1078-0432.CCR-18-3517.
PMID
30952643
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
25
Issue
13
Publish Date
2019
Start Page
4155
End Page
4167
DOI
10.1158/1078-0432.CCR-18-3517

Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation-Induced Hematopoietic Injury.

PURPOSE: Extracellular vesicles (EVs) are shed vesicles that bear a combination of nucleic acids and proteins. EVs are becoming recognized as a mode of cell-to-cell communication. Because hematopoietic stem cells reside in proximity to endothelial cells (ECs), we investigated whether EC-derived EVs could regulate hematopoietic stem cell regeneration after ionizing radiation. METHODS AND MATERIALS: We generated EVs derived from primary murine marrow ECs. We sought to determine the response of irradiated hematopoietic stem and progenitor cells to syngeneic or allogeneic EVs in culture assays. Starting 24 hours after either sublethal or lethal irradiation, mice were treated with EVs or saline or cultured primary marrow endothelial cells to determine the hematopoietic response in vivo. RESULTS: We demonstrate that EVs bear nuclear material and express EC-specific markers. Treatment with EVs promoted cell expansion and increased the number of colony-forming units compared to irradiated, hematopoietic cell cultures treated with cytokines alone. After total body irradiation, EV-treated mice displayed preserved marrow cellularity, marrow vessel integrity, and prolonged overall survival compared with controls treated with saline. Treatment of irradiated hematopoietic stem/progenitor cells (HSPCs) with EVs from different genetic strains showed results similar to treatment of HSPCs from syngeneic EVs. Mechanistically, treatment of irradiated HSPCs with EVs resulted in decreased levels of annexin V+ apoptotic cell death, which is mediated in part by tissue inhibitor of metalloproteinase-1. CONCLUSIONS: Our findings show that syngeneic or allogeneic EVs could serve as cell-derived therapy to deliver physiologic doses of nucleic acids and growth factors to hematopoietic cells to accelerate hematopoietic regeneration.

Authors
Piryani, SO; Jiao, Y; Kam, AYF; Liu, Y; Vo-Dinh, T; Chen, BJ; Chao, NJ; Doan, PL
MLA Citation
Piryani, Sadhna O., et al. “Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation-Induced Hematopoietic Injury..” Int J Radiat Oncol Biol Phys, vol. 104, no. 2, June 2019, pp. 291–301. Pubmed, doi:10.1016/j.ijrobp.2019.02.008.
PMID
30763662
Source
pubmed
Published In
Int J Radiat Oncol Biol Phys
Volume
104
Issue
2
Publish Date
2019
Start Page
291
End Page
301
DOI
10.1016/j.ijrobp.2019.02.008

Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation-Induced Hematopoietic Injury

Authors
Piryani, SO; Jiao, Y; Kam, AYF; Liu, Y; Tuan, V-D; Chen, BJ; Chao, NJ; Doan, PL
MLA Citation
Piryani, Sadhna O., et al. “Endothelial Cell-Derived Extracellular Vesicles Mitigate Radiation-Induced Hematopoietic Injury.” Blood, vol. 132, AMER SOC HEMATOLOGY, 2018. Wos, doi:10.1182/blood-2018-99-117058.
Source
wos
Published In
Blood
Volume
132
Publish Date
2018
DOI
10.1182/blood-2018-99-117058

Epidermal Growth Factor and Granulocyte Colony Stimulating Factor Signaling Are Synergistic for Hematopoietic Regeneration.

Hematopoietic regeneration following chemotherapy may be distinct from regeneration following radiation. While we have shown that epidermal growth factor (EGF) accelerates regeneration following radiation, its role following chemotherapy is currently unknown. We sought to identify EGF as a hematopoietic growth factor for chemotherapy-induced myelosuppression. Following 5-fluorouracil (5-FU), EGF accelerated hematopoietic stem cell regeneration and prolonged survival compared with saline-treated mice. To mitigate chemotherapy-induced injury to endothelial cells in vivo, we deleted Bax in VEcadherin+ cells (VEcadherinCre;BaxFL/FL mice). Following 5-FU, VEcadherinCre;BaxFL/FL mice displayed preserved hematopoietic stem/progenitor content compared with littermate controls. 5-FU and EGF treatment resulted in increased cellular proliferation, decreased apoptosis, and increased DNA double-strand break repair by non-homologous end-joining recombination compared with saline-treated control mice. When granulocyte colony stimulating factor (G-CSF) is given with EGF, this combination was synergistic for regeneration compared with either G-CSF or EGF alone. EGF increased G-CSF receptor (G-CSFR) expression following 5-FU. Conversely, G-CSF treatment increased both EGF receptor (EGFR) and phosphorylation of EGFR in hematopoietic stem/progenitor cells. In humans, the expression of EGFR is increased in patients with colorectal cancer treated with 5-FU compared with cancer patients not on 5-FU. Similarly, EGFR signaling is responsive to G-CSF in humans in vivo with both increased EGFR and phospho-EGFR in healthy human donors following G-CSF treatment compared with donors who did not receive G-CSF. These data identify EGF as a hematopoietic growth factor following myelosuppressive chemotherapy and that dual therapy with EGF and G-CSF may be an effective method to accelerate hematopoietic regeneration. Stem Cells 2018;36:252-264.

Authors
Piryani, SO; Kam, AYF; Kliassov, EG; Chen, BJ; Spector, NL; Chute, JP; Hsu, DS; Chao, NJ; Doan, PL
MLA Citation
Piryani, Sadhna O., et al. “Epidermal Growth Factor and Granulocyte Colony Stimulating Factor Signaling Are Synergistic for Hematopoietic Regeneration..” Stem Cells, vol. 36, no. 2, Feb. 2018, pp. 252–64. Pubmed, doi:10.1002/stem.2731.
PMID
29086459
Source
pubmed
Published In
Stem Cells
Volume
36
Issue
2
Publish Date
2018
Start Page
252
End Page
264
DOI
10.1002/stem.2731

Clinical Outcomes of Microtransplantation for Older Adults with Acute Myeloid Leukemia

Authors
Sung, AD; de Castro, CM; LeBlanc, TW; Long, GD; Adams, DB; Brander, DM; Dave, S; Diehl, LF; Phuong, LD; Hennig, T; Kang, Y; McKinney, MS; Rein, LAM; Sipkins, DA; Yang, Y; Chao, NJ; Rizzieri, DA
MLA Citation
Sung, Anthony D., et al. “Clinical Outcomes of Microtransplantation for Older Adults with Acute Myeloid Leukemia.” Blood, vol. 130, AMER SOC HEMATOLOGY, 2017.
Source
wos
Published In
Blood
Volume
130
Publish Date
2017

Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice.

BACKGROUND: Radiation exposure poses a significant threat to public health. Hematopoietic injury is one of the major manifestations of acute radiation sickness. Protection and/or mitigation of hematopoietic stem cells (HSCs) from radiation injury is an important goal in the development of medical countermeasure agents (MCM). We recently identified thioredoxin (TXN) as a novel molecule that has marked protective and proliferative effects on HSCs. In the current study, we investigated the effectiveness of TXN in rescuing mice from a lethal dose of total body radiation (TBI) and in enhancing hematopoietic reconstitution following a lethal dose of irradiation. METHODS: We used in-vivo and in-vitro methods to understand the biological and molecular mechanisms of TXN on radiation mitigation. BABL/c mice were used for the survival study and a flow cytometer was used to quantify the HSC population and cell senescence. A hematology analyzer was used for the peripheral blood cell count, including white blood cells (WBCs), red blood cells (RBCs), hemoglobin, and platelets. Colony forming unit (CFU) assay was used to study the colongenic function of HSCs. Hematoxylin and eosin staining was used to determine the bone marrow cellularity. Senescence-associated β-galactosidase assay was used for cell senescence. Western blot analysis was used to evaluate the DNA damage and senescence protein expression. Immunofluorescence staining was used to measure the expression of γ-H2AX foci for DNA damage. RESULTS: We found that administration of TXN 24 h following irradiation significantly mitigates BALB/c mice from TBI-induced death: 70% of TXN-treated mice survived, whereas only 25% of saline-treated mice survived. TXN administration led to enhanced recovery of peripheral blood cell counts, bone marrow cellularity, and HSC population as measured by c-Kit+Sca-1+Lin- (KSL) cells, SLAM + KSL cells and CFUs. TXN treatment reduced cell senescence and radiation-induced double-strand DNA breaks in both murine bone marrow lineage-negative (Lin-) cells and primary fibroblasts. Furthermore, TXN decreased the expression of p16 and phosphorylated p38. Our data suggest that TXN modulates diverse cellular processes of HSCs. CONCLUSIONS: Administration of TXN 24 h following irradiation mitigates radiation-induced lethality. To the best of our knowledge, this is the first report demonstrating that TXN reduces radiation-induced lethality. TXN shows potential utility in the mitigation of radiation-induced hematopoietic injury.

Authors
Sundaramoorthy, P; Wang, Q; Zheng, Z; Jiao, Y; Chen, BJ; Doan, PL; Chao, NJ; Kang, Y
MLA Citation
Sundaramoorthy, Pasupathi, et al. “Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice..” Stem Cell Res Ther, vol. 8, no. 1, Nov. 2017. Pubmed, doi:10.1186/s13287-017-0711-2.
PMID
29141658
Source
pubmed
Published In
Stem Cell Research & Therapy
Volume
8
Issue
1
Publish Date
2017
Start Page
263
DOI
10.1186/s13287-017-0711-2

Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration.

Hematopoietic stem and progenitor cells (HSPCs) are predominantly quiescent in adults, but proliferate in response to bone marrow (BM) injury. Here, we show that deletion of Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) promotes HSPC regeneration and hematopoietic recovery following radiation injury. Using Camkk2-enhanced green fluorescent protein (EGFP) reporter mice, we found that Camkk2 expression is developmentally regulated in HSPC. Deletion of Camkk2 in HSPC results in a significant downregulation of genes affiliated with the quiescent signature. Accordingly, HSPC from Camkk2 null mice have a high proliferative capability when stimulated in vitro in the presence of BM-derived endothelial cells. In addition, Camkk2 null mice are more resistant to radiation injury and show accelerated hematopoietic recovery, enhanced HSPC regeneration and ultimately a prolonged survival following sublethal or lethal total body irradiation. Mechanistically, we propose that CaMKK2 regulates the HSPC response to hematopoietic damage by coupling radiation signaling to activation of the anti-proliferative AMP-activated protein kinase. Finally, we demonstrated that systemic administration of the small molecule CaMKK2 inhibitor, STO-609, to irradiated mice enhanced HSPC recovery and improved survival. These findings identify CaMKK2 as an important regulator of HSPC regeneration and demonstrate CaMKK2 inhibition is a novel approach to promoting hematopoietic recovery after BM injury.

Authors
Racioppi, L; Lento, W; Huang, W; Arvai, S; Doan, PL; Harris, JR; Marcon, F; Nakaya, HI; Liu, Y; Chao, N
MLA Citation
Racioppi, Luigi, et al. “Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration..” Cell Death Dis, vol. 8, no. 10, Oct. 2017. Pubmed, doi:10.1038/cddis.2017.474.
PMID
28981105
Source
pubmed
Published In
Cell Death & Disease
Volume
8
Issue
10
Publish Date
2017
Start Page
e3076
DOI
10.1038/cddis.2017.474

Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms.

The role of osteolineage cells in regulating hematopoietic stem cell (HSC) regeneration following myelosuppression is not well understood. Here we show that deletion of the pro-apoptotic genes Bak and Bax in osterix (Osx, also known as Sp7 transcription factor 7)-expressing cells in mice promotes HSC regeneration and hematopoietic radioprotection following total body irradiation. These mice showed increased bone marrow (BM) levels of the protein dickkopf-1 (Dkk1), which was produced in Osx-expressing BM cells. Treatment of irradiated HSCs with Dkk1 in vitro increased the recovery of both long-term repopulating HSCs and progenitor cells, and systemic administration of Dkk1 to irradiated mice increased hematopoietic recovery and improved survival. Conversely, inducible deletion of one allele of Dkk1 in Osx-expressing cells in adult mice inhibited the recovery of BM stem and progenitor cells and of complete blood counts following irradiation. Dkk1 promoted hematopoietic regeneration via both direct effects on HSCs, in which treatment with Dkk1 decreased the levels of mitochondrial reactive oxygen species and suppressed senescence, and indirect effects on BM endothelial cells, in which treatment with Dkk1 induced epidermal growth factor (EGF) secretion. Accordingly, blockade of the EGF receptor partially abrogated Dkk1-mediated hematopoietic recovery. These data identify Dkk1 as a regulator of hematopoietic regeneration and demonstrate paracrine cross-talk between BM osteolineage cells and endothelial cells in regulating hematopoietic reconstitution following injury.

Authors
Himburg, HA; Doan, PL; Quarmyne, M; Yan, X; Sasine, J; Zhao, L; Hancock, GV; Kan, J; Pohl, KA; Tran, E; Chao, NJ; Harris, JR; Chute, JP
MLA Citation
Himburg, Heather A., et al. “Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms..” Nat Med, vol. 23, no. 1, Jan. 2017, pp. 91–99. Pubmed, doi:10.1038/nm.4251.
PMID
27918563
Source
pubmed
Published In
Nat Med
Volume
23
Issue
1
Publish Date
2017
Start Page
91
End Page
99
DOI
10.1038/nm.4251

EGF Accelerates Hematopoietic Stem Cell Regeneration Following 5-FU Chemotherapy Via G-CSF Receptor Signaling

Authors
Piryani, SO; Kam, AYF; Kliassov, EG; Chen, BJ; Spector, NL; Chute, JP; Chao, NJ; Doan, PL
MLA Citation
Piryani, Sadhna O., et al. “EGF Accelerates Hematopoietic Stem Cell Regeneration Following 5-FU Chemotherapy Via G-CSF Receptor Signaling.” Blood, vol. 128, no. 22, AMER SOC HEMATOLOGY, 2016.
Source
wos
Published In
Blood
Volume
128
Issue
22
Publish Date
2016

Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.

Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10+/+ mice. After total body irradiation (TBI), Grb10m/+ mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10+/+ mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo.

Authors
Yan, X; Himburg, HA; Pohl, K; Quarmyne, M; Tran, E; Zhang, Y; Fang, T; Kan, J; Chao, NJ; Zhao, L; Doan, PL; Chute, JP
MLA Citation
Yan, Xiao, et al. “Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration..” Cell Rep, vol. 17, no. 6, Nov. 2016, pp. 1584–94. Pubmed, doi:10.1016/j.celrep.2016.10.025.
Website
http://hdl.handle.net/10161/14158
PMID
27806297
Source
pubmed
Published In
Cell Reports
Volume
17
Issue
6
Publish Date
2016
Start Page
1584
End Page
1594
DOI
10.1016/j.celrep.2016.10.025

Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal and Regeneration Via Control of mTOR Signaling

Authors
Chute, JP; Yan, X; Himburg, HA; Doan, PL; Quarmyne, M; Tran, E; Chao, NJ; Zhao, L
MLA Citation
Chute, John P., et al. “Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal and Regeneration Via Control of mTOR Signaling.” Biology of Blood and Marrow Transplantation, vol. 22, no. 3, Elsevier BV, 2016, pp. S426–S426. Crossref, doi:10.1016/j.bbmt.2015.11.971.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
Volume
22
Issue
3
Publish Date
2016
Start Page
S426
End Page
S426
DOI
10.1016/j.bbmt.2015.11.971

Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal Via Control of mTOR Signaling

Authors
Yan, X; Himburg, HA; Doan, PL; Quarmyne, M; Tran, E; Zhao, L; Chao, NJ; Chute, JP
MLA Citation
Yan, Xiao, et al. “Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal Via Control of mTOR Signaling.” Blood, vol. 126, no. 23, AMER SOC HEMATOLOGY, 2015.
Source
wos
Published In
Blood
Volume
126
Issue
23
Publish Date
2015

Dickkopf 1 (Dkk1) Regulates Hematopoietic Stem Cell Regeneration

Authors
Himburg, HA; Doan, PL; Yan, X; Quarmyne, M; Zhao, L; Tran, E; Chao, NJ; Harris, J; Chute, JP
MLA Citation
Himburg, Heather A., et al. “Dickkopf 1 (Dkk1) Regulates Hematopoietic Stem Cell Regeneration.” Blood, vol. 126, no. 23, AMER SOC HEMATOLOGY, 2015.
Source
wos
Published In
Blood
Volume
126
Issue
23
Publish Date
2015

Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity.

Hematopoietic stem cell (HSC) function is regulated by activation of receptor tyrosine kinases (RTKs). Receptor protein tyrosine phosphatases (PTPs) counterbalance RTK signaling; however, the functions of receptor PTPs in HSCs remain incompletely understood. We found that a receptor PTP, PTPσ, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTPσ-deficient mice revealed that the loss of PTPσ substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTPσ-deficient mice had no apparent alterations in cell-cycle status, apoptosis, or homing capacity, these HSCs exhibited increased levels of activated RAC1, a RhoGTPase that regulates HSC engraftment capacity. shRNA-mediated silencing of PTPσ also increased activated RAC1 levels in wild-type HSCs. Functionally, PTPσ-deficient BM cells displayed increased cobblestone area-forming cell (CAFC) capacity and augmented transendothelial migration capacity, which was abrogated by RAC inhibition. Specific selection of human cord blood CD34⁺CD38⁻CD45RA⁻lin⁻ PTPσ⁻ cells substantially increased the repopulating capacity of human HSCs compared with CD34⁺CD38⁻CD45RA⁻lin⁻ cells and CD34⁺CD38⁻CD45RA⁻lin⁻PTPσ⁺ cells. Our results demonstrate that PTPσ regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTPσ-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation.

Authors
Quarmyne, M; Doan, PL; Himburg, HA; Yan, X; Nakamura, M; Zhao, L; Chao, NJ; Chute, JP
MLA Citation
Quarmyne, Mamle, et al. “Protein tyrosine phosphatase-σ regulates hematopoietic stem cell-repopulating capacity..” J Clin Invest, vol. 125, no. 1, Jan. 2015, pp. 177–82. Pubmed, doi:10.1172/JCI77866.
Website
http://hdl.handle.net/10161/14160
PMID
25415437
Source
pubmed
Published In
J Clin Invest
Volume
125
Issue
1
Publish Date
2015
Start Page
177
End Page
182
DOI
10.1172/JCI77866

Protein Tyrosine Phosphatase-Sigma (PTP sigma) Regulates Hematopoietic Stem Cell Repopulating Capacity

Authors
Quarmyne, M; Doan, PL; Himburg, HA; Yan, X; Zhao, L; Chao, NJ; Chute, JP
MLA Citation
Quarmyne, Mamle, et al. “Protein Tyrosine Phosphatase-Sigma (PTP sigma) Regulates Hematopoietic Stem Cell Repopulating Capacity.” Blood, vol. 124, no. 21, AMER SOC HEMATOLOGY, 2014.
Source
wos
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell Renewal

Authors
Yan, X; Himburg, HA; Doan, PL; Quarmyne, M; Chao, NJ; Chute, JP
MLA Citation
Yan, Xiao, et al. “Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell Renewal.” Blood, vol. 124, no. 21, AMER SOC HEMATOLOGY, 2014.
Source
wos
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

Calcium Calmodulin Dependent Kinase Kinase 2 Regulates Hematopoietic Stem Cell Regeneration and Quiescence

Authors
Lento, W; Huang, W; Phuong, D; Chao, NJ; Racioppi, L
MLA Citation
Lento, William, et al. “Calcium Calmodulin Dependent Kinase Kinase 2 Regulates Hematopoietic Stem Cell Regeneration and Quiescence.” Blood, vol. 124, no. 21, AMER SOC HEMATOLOGY, 2014.
Source
wos
Published In
Blood
Volume
124
Issue
21
Publish Date
2014

Pleiotrophin mediates hematopoietic regeneration via activation of RAS.

Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner.

Authors
Himburg, HA; Yan, X; Doan, PL; Quarmyne, M; Micewicz, E; McBride, W; Chao, NJ; Slamon, DJ; Chute, JP
MLA Citation
Himburg, Heather A., et al. “Pleiotrophin mediates hematopoietic regeneration via activation of RAS..” J Clin Invest, vol. 124, no. 11, Nov. 2014, pp. 4753–58. Pubmed, doi:10.1172/JCI76838.
PMID
25250571
Source
pubmed
Published In
J Clin Invest
Volume
124
Issue
11
Publish Date
2014
Start Page
4753
End Page
4758
DOI
10.1172/JCI76838

Ex vivo expansion of murine and human hematopoietic stem cells.

Hematopoietic stem cells have the capacity to self-renew and give rise to the entirety of the mature blood and immune system throughout the lifespan of an organism. Here, we describe methods to isolate and culture murine bone marrow (BM) CD34(-)ckit(+)Sca1(+)Lineage(-) (CD34(-)KSL) hematopoietic stem cells (HSCs). We also describe a method to measure functional HSC content via the competitive repopulation assay. Furthermore, we summarize methods to isolate and culture human CD34(+)CD38(-)Lineage(-) cells which are enriched for human hematopoietic stem and progenitor cells.

Authors
Doan, PL; Chute, JP
MLA Citation
Doan, Phuong L., and John P. Chute. “Ex vivo expansion of murine and human hematopoietic stem cells..” Methods Mol Biol, vol. 1185, 2014, pp. 211–21. Pubmed, doi:10.1007/978-1-4939-1133-2_14.
Website
http://hdl.handle.net/10161/14159
PMID
25062631
Source
pubmed
Published In
Methods Mol Biol
Volume
1185
Publish Date
2014
Start Page
211
End Page
221
DOI
10.1007/978-1-4939-1133-2_14

Ex vivo expansion of murine and human hematopoietic stem cells

Hematopoietic stem cells have the capacity to self-renew and give rise to the entirety of the mature blood and immune system throughout the lifespan of an organism. Here, we describe methods to isolate and culture murine bone marrow (BM) CD34-ckit+Sca1+Lineage- (CD34-KSL) hematopoietic stem cells (HSCs). We also describe a method to measure functional HSC content via the competitive repopulation assay. Furthermore, we summarize methods to isolate and culture human CD34 +CD38-Lineage- cells which are enriched for human hematopoietic stem and progenitor cells. © 2014 Springer Science+Business Media New York.

Authors
Doan, PL; Chute, JP
MLA Citation
Doan, P. L., and J. P. Chute. “Ex vivo expansion of murine and human hematopoietic stem cells.” Methods in Molecular Biology, vol. 1185, Humana Press Inc., 2014, pp. 211–21. Scopus, doi:10.1007/978-1-4939-1133-2-14.
Website
http://hdl.handle.net/10161/14157
Source
scopus
Published In
Methods in Molecular Biology (Clifton, N.J.)
Volume
1185
Publish Date
2014
Start Page
211
End Page
221
DOI
10.1007/978-1-4939-1133-2-14

Pleiotrophin Improves Survival Following Radiation-Induced Myelosuppression and Mediates HSC Expansion Via Induction Of Ras Signaling

Authors
Himburg, HA; Doan, PL; Quarmyne, M; Nakamura, M; Chao, NJ; Chute, JP
MLA Citation
Himburg, Heather A., et al. “Pleiotrophin Improves Survival Following Radiation-Induced Myelosuppression and Mediates HSC Expansion Via Induction Of Ras Signaling.” Blood, vol. 122, no. 21, AMER SOC HEMATOLOGY, 2013.
Source
wos
Published In
Blood
Volume
122
Issue
21
Publish Date
2013

Epidermal growth factor regulates hematopoietic regeneration after radiation injury.

The mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow serum of mice bearing deletion of Bak and Bax in TIE2-expressing cells in Tie2Cre; Bak1(-/-); Bax(flox/-) mice. These mice showed radioprotection of the HSC pool and 100% survival after a lethal dose of total-body irradiation (TBI). Bone marrow HSCs from wild-type mice expressed functional EGF receptor (EGFR), and systemic administration of EGF promoted the recovery of the HSC pool in vivo and improved the survival of mice after TBI. Conversely, administration of erlotinib, an EGFR antagonist, decreased both HSC regeneration and the survival of mice after TBI. Mice with EGFR deficiency in VAV-expressing hematopoietic cells also had delayed recovery of bone marrow stem and progenitor cells after TBI. Mechanistically, EGF reduced radiation-induced apoptosis of HSCs and mediated this effect through repression of the proapoptotic protein PUMA. Our findings show that EGFR signaling regulates HSC regeneration after myelosuppressive injury.

Authors
Doan, PL; Himburg, HA; Helms, K; Russell, JL; Fixsen, E; Quarmyne, M; Harris, JR; Deoliviera, D; Sullivan, JM; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, Phuong L., et al. “Epidermal growth factor regulates hematopoietic regeneration after radiation injury..” Nat Med, vol. 19, no. 3, Mar. 2013, pp. 295–304. Pubmed, doi:10.1038/nm.3070.
Website
http://hdl.handle.net/10161/14156
PMID
23377280
Source
pubmed
Published In
Nat Med
Volume
19
Issue
3
Publish Date
2013
Start Page
295
End Page
304
DOI
10.1038/nm.3070

Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury.

Hematopoietic stem cells (HSCs) reside in proximity to bone marrow endothelial cells (BM ECs) and maintenance of the HSC pool is dependent upon EC-mediated c-kit signaling. Here, we used genetic models to determine whether radioprotection of BM ECs could facilitate hematopoietic regeneration following radiation-induced myelosuppression. We developed mice bearing deletion of the proapoptotic proteins, BAK and BAX, in Tie2(+) ECs and HSCs (Tie2Bak/Bax(Fl/-) mice) and compared their hematopoietic recovery following total body irradiation (TBI) with mice which retained Bax in Tie2(+) cells. Mice bearing deletion of Bak and Bax in Tie2(+) cells demonstrated protection of BM HSCs, preserved BM vasculature, and 100% survival following lethal dose TBI. In contrast, mice that retained Bax expression in Tie2(+) cells demonstrated depletion of BM HSCs, disrupted BM vasculature, and 10% survival post-TBI. In a complementary study, VEcadherinBak/Bax(Fl/-) mice, which lack Bak and Bax in VEcadherin(+) ECs, also demonstrated increased recovery of BM stem/progenitor cells following TBI compared to mice which retained Bax in VEcadherin(+) ECs. Importantly, chimeric mice that lacked Bak and Bax in HSCs but retained Bak and Bax in BM ECs displayed significantly decreased HSC content and survival following TBI compared to mice lacking Bak and Bax in both HSCs and BM ECs. These data suggest that the hematopoietic response to ionizing radiation is dependent upon HSC-autonomous responses but is regulated by BM EC-mediated mechanisms. Therefore, BM ECs may be therapeutically targeted as a means to augment hematopoietic reconstitution following myelosuppression.

Authors
Doan, PL; Russell, JL; Himburg, HA; Helms, K; Harris, JR; Lucas, J; Holshausen, KC; Meadows, SK; Daher, P; Jeffords, LB; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, Phuong L., et al. “Tie2(+) bone marrow endothelial cells regulate hematopoietic stem cell regeneration following radiation injury..” Stem Cells, vol. 31, no. 2, Feb. 2013, pp. 327–37. Pubmed, doi:10.1002/stem.1275.
PMID
23132593
Source
pubmed
Published In
Stem Cells
Volume
31
Issue
2
Publish Date
2013
Start Page
327
End Page
337
DOI
10.1002/stem.1275

Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche

Authors
Himburg, HA; Harris, JR; Ito, T; Daher, P; Russell, JL; Quarmyne, M; Doan, PL; Helms, K; Nakamura, M; Fixsen, E; Herradon, G; Reya, T; Chao, NJ; Harroch, S; Chute, JP
MLA Citation
Himburg, H. A., et al. “Pleiotrophin Regulates the Retention and Self-Renewal of Hematopoietic Stem Cells in the Bone Marrow Vascular Niche.” Cell Reports, vol. 2, no. 6, Dec. 2012. Scopus, doi:10.1016/j.celrep.2012.11.005.
Source
scopus
Published In
Cell Reports
Volume
2
Issue
6
Publish Date
2012
Start Page
1774
DOI
10.1016/j.celrep.2012.11.005

Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche.

The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth factor pleiotrophin (PTN) in regulating HSC function in the niche. PTN(-/-) mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo.

Authors
Himburg, HA; Harris, JR; Ito, T; Daher, P; Russell, JL; Quarmyne, M; Doan, PL; Helms, K; Nakamura, M; Fixsen, E; Herradon, G; Reya, T; Chao, NJ; Harroch, S; Chute, JP
MLA Citation
Himburg, Heather A., et al. “Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche..” Cell Rep, vol. 2, no. 4, Oct. 2012, pp. 964–75. Pubmed, doi:10.1016/j.celrep.2012.09.002.
PMID
23084748
Source
pubmed
Published In
Cell Reports
Volume
2
Issue
4
Publish Date
2012
Start Page
964
End Page
975
DOI
10.1016/j.celrep.2012.09.002

Improved time to progression for transarterial chemoembolization compared with transarterial embolization for patients with unresectable hepatocellular carcinoma.

BACKGROUND: Embolizing branches of the hepatic artery lengthens survival for patients with unresectable hepatocellular carcinoma (HCC), but the benefit of combining chemotherapy with the embolizing particles remains controversial. METHODS: A retrospective review was undertaken of sequential patients with advanced HCC undergoing embolization in the past 10 years at 2 neighboring institutions and with 2 years of follow-up data. TACE was generally performed with doxorubicin plus mitomycin C. RESULTS: One hundred twenty-four patients were included; 77 received TACE and 47 received TAE. On multivariable analysis stratified by institution, type of embolization and CLIP score significantly predicted PFS and time to progression (TTP), whereas CLIP score and AFP independently predicted overall survival (OS). TACE significantly prolonged PFS and TTP (P = .0004 and P = .001, respectively), but not OS (P = .83). CONCLUSIONS: The addition of chemotherapy to TAE prolongs PFS and TTP. Future efforts should focus on adjunctive therapies after the embolization to increase survival.

Authors
Morse, MA; Hanks, BA; Suhocki, P; Doan, PL; Liu, EA; Frost, P; Bernard, SA; Tsai, A; Moore, DT; O'Neil, BH
MLA Citation
Morse, Michael A., et al. “Improved time to progression for transarterial chemoembolization compared with transarterial embolization for patients with unresectable hepatocellular carcinoma..” Clin Colorectal Cancer, vol. 11, no. 3, Sept. 2012, pp. 185–90. Pubmed, doi:10.1016/j.clcc.2011.11.003.
PMID
22280845
Source
pubmed
Published In
Clinical Colorectal Cancer
Volume
11
Issue
3
Publish Date
2012
Start Page
185
End Page
190
DOI
10.1016/j.clcc.2011.11.003

Egf Signaling Regulates Hematopoietic Regeneration Following Total Body Irradiation

Authors
Doan, PL; Russell, JL; Himburg, HA; Helms, K; Sullivan, JM; Jeffords, LB; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, P. L., et al. “Egf Signaling Regulates Hematopoietic Regeneration Following Total Body Irradiation.” Biology of Blood and Marrow Transplantation, vol. 18, no. 2, Elsevier BV, 2012, pp. S235–S235. Crossref, doi:10.1016/j.bbmt.2011.12.497.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
Volume
18
Issue
2
Publish Date
2012
Start Page
S235
End Page
S235
DOI
10.1016/j.bbmt.2011.12.497

Pleiotrophin Regulates Normal and Leukemic Hematopoietic Stem Cell Fate

Authors
Himburg, HA; Ito, T; Harris, JR; Quarmyne, M; Helms, KL; Doan, PL; Reya, T; Chao, NJ; Chute, JP
MLA Citation
Himburg, H. A., et al. “Pleiotrophin Regulates Normal and Leukemic Hematopoietic Stem Cell Fate.” Biology of Blood and Marrow Transplantation, vol. 18, no. 2, Elsevier BV, 2012, pp. S236–S236. Crossref, doi:10.1016/j.bbmt.2011.12.498.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
Volume
18
Issue
2
Publish Date
2012
Start Page
S236
End Page
S236
DOI
10.1016/j.bbmt.2011.12.498

The vascular niche: home for normal and malignant hematopoietic stem cells.

Hematopoietic stem cells (HSCs) are uniquely capable of self-renewal and provision of all of the mature elements of the blood and immune system throughout the lifetime of an individual. HSC self-renewal is regulated by both intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments or 'niches' wherein HSCs reside. HSCs have been shown to reside in close association with bone marrow (BM) osteoblasts in the endosteal niche and also in proximity to BM sinusoidal vessels. An unresolved question surrounds whether the endosteal and vascular niches provide synchronous or redundant regulation of HSC fate or whether these niches provide wholly unique regulatory functions. Furthermore, while some aspects of the mechanisms through which osteoblasts regulate HSC fate have been defined, the mechanisms through which the vascular niche regulates HSC fate remain obscure. Here, we summarize the anatomic and functional basis supporting the concept of an HSC vascular niche as well as the precise function of endothelial cells, perivascular cells and stromal cells within the niche in regulating HSC fate. Lastly, we will highlight the role of the vascular niche in regulating leukemic stem cell fate in vivo.

Authors
Doan, PL; Chute, JP
MLA Citation
Doan, P. L., and J. P. Chute. “The vascular niche: home for normal and malignant hematopoietic stem cells..” Leukemia, vol. 26, no. 1, Jan. 2012, pp. 54–62. Pubmed, doi:10.1038/leu.2011.236.
PMID
21886170
Source
pubmed
Published In
Leukemia
Volume
26
Issue
1
Publish Date
2012
Start Page
54
End Page
62
DOI
10.1038/leu.2011.236

High Dose BCNU/Melphalan Preparative Regimen Doubles Event Free Survival of Myeloma Patients Undergoing Autologous Transplantation

Authors
Gasparetto, C; Bacon, WA; Doan, P; Rizzieri, DA; Horwitz, ME; Chute, JP; Sullivan, KM; Yopp, A; Li, Z; Chao, NJ; Long, GD
MLA Citation
Gasparetto, Cristina, et al. “High Dose BCNU/Melphalan Preparative Regimen Doubles Event Free Survival of Myeloma Patients Undergoing Autologous Transplantation.” Blood, vol. 118, no. 21, AMER SOC HEMATOLOGY, 2011, pp. 879–879.
Source
wos
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
879
End Page
879

Tie2+ Endothelial Cells Mediate Hematopoietic Stem Cell Regeneration Via EGF Signaling

Authors
Doan, PL; Russell, JL; Himburg, HA; Helms, K; Meadows, SK; Daher, P; Sullivan, JM; Jeffords, LB; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, P. L., et al. “Tie2+ Endothelial Cells Mediate Hematopoietic Stem Cell Regeneration Via EGF Signaling.” Biology of Blood and Marrow Transplantation, vol. 17, no. 2, Elsevier BV, 2011, pp. S188–S188. Crossref, doi:10.1016/j.bbmt.2010.12.107.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
Volume
17
Issue
2
Publish Date
2011
Start Page
S188
End Page
S188
DOI
10.1016/j.bbmt.2010.12.107

Pleiotrophin Signaling Is Necessary for Hematopoietic Stem Cell Self Renewal and Is Regulated by the Bone Marrow Microenvironment

Authors
Himburg, HA; Daher, P; Russell, L; Doan, P; Quarmyne, M; Meadows, S; Herradon, G; Chao, NJ; Chute, JP
MLA Citation
Himburg, H. A., et al. “Pleiotrophin Signaling Is Necessary for Hematopoietic Stem Cell Self Renewal and Is Regulated by the Bone Marrow Microenvironment.” Biology of Blood and Marrow Transplantation, vol. 17, no. 2, Elsevier BV, 2011, pp. S149–S149. Crossref, doi:10.1016/j.bbmt.2010.12.002.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
Volume
17
Issue
2
Publish Date
2011
Start Page
S149
End Page
S149
DOI
10.1016/j.bbmt.2010.12.002

VE Cadherin Positive Endothelial Cells Regulate Hematopoietic Reconstitution In Vivo

Authors
Russell, JL; Doan, P; Himburg, HA; Meadows, SK; Daher, P; Helms, K; Quarmyne, M; Chao, NJ; Kirsch, D; Chute, JP
MLA Citation
Russell, J. Lauren, et al. “VE Cadherin Positive Endothelial Cells Regulate Hematopoietic Reconstitution In Vivo.” Blood, vol. 116, no. 21, AMER SOC HEMATOLOGY, 2010, pp. 1532–1532.
Source
wos
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1532
End Page
1532

Pleiotrophin Signaling Is Necessary and Sufficient for Hematopoietic Stem Cell Self-Renewal In Vivo

Authors
Himburg, HA; Daher, P; Russell, JL; Doan, P; Quarmyne, M; Meadows, SK; Helms, K; Herradon, G; Chao, NJ; Chute, JP
MLA Citation
Himburg, Heather A., et al. “Pleiotrophin Signaling Is Necessary and Sufficient for Hematopoietic Stem Cell Self-Renewal In Vivo.” Blood, vol. 116, no. 21, AMER SOC HEMATOLOGY, 2010, pp. 180–180.
Source
wos
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
180
End Page
180

Facilitation of Hematopoietic Reconstitution Via Inhibition of Bone Marrow Endothelial Cell-Mediated SDF-1 Signaling

Authors
Doan, PL; Russell, JL; Himburg, HA; Meadows, SK; Daher, P; Helms, K; Quarmyne, M; Harris, JR; Reya, T; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, Phuong L., et al. “Facilitation of Hematopoietic Reconstitution Via Inhibition of Bone Marrow Endothelial Cell-Mediated SDF-1 Signaling.” Blood, vol. 116, no. 21, AMER SOC HEMATOLOGY, 2010, pp. 1578–1578.
Source
wos
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1578
End Page
1578

Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles.

In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79-100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16-43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.

Authors
Meadows, SK; Dressman, HK; Daher, P; Himburg, H; Russell, JL; Doan, P; Chao, NJ; Lucas, J; Nevins, JR; Chute, JP
MLA Citation
Meadows, Sarah K., et al. “Diagnosis of partial body radiation exposure in mice using peripheral blood gene expression profiles..” Plos One, vol. 5, no. 7, July 2010. Pubmed, doi:10.1371/journal.pone.0011535.
Website
http://hdl.handle.net/10161/4550
PMID
20634956
Source
pubmed
Published In
Plos One
Volume
5
Issue
7
Publish Date
2010
Start Page
e11535
DOI
10.1371/journal.pone.0011535

Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells.

Hematopoietic stem cell (HSC) self-renewal is regulated by both intrinsic and extrinsic signals. Although some of the pathways that regulate HSC self-renewal have been uncovered, it remains largely unknown whether these pathways can be triggered by deliverable growth factors to induce HSC growth or regeneration. Here we show that pleiotrophin, a neurite outgrowth factor with no known function in hematopoiesis, efficiently promotes HSC expansion in vitro and HSC regeneration in vivo. Treatment of mouse bone marrow HSCs with pleiotrophin caused a marked increase in long-term repopulating HSC numbers in culture, as measured in competitive repopulating assays. Treatment of human cord blood CD34(+)CDCD38(-)Lin(-) cells with pleiotrophin also substantially increased severe combined immunodeficient (SCID)-repopulating cell counts in culture, compared to input and cytokine-treated cultures. Systemic administration of pleiotrophin to irradiated mice caused a pronounced expansion of bone marrow stem and progenitor cells in vivo, indicating that pleiotrophin is a regenerative growth factor for HSCs. Mechanistically, pleiotrophin activated phosphoinositide 3-kinase (PI3K) signaling in HSCs; antagonism of PI3K or Notch signaling inhibited pleiotrophin-mediated expansion of HSCs in culture. We identify the secreted growth factor pleiotrophin as a new regulator of both HSC expansion and regeneration.

Authors
Himburg, HA; Muramoto, GG; Daher, P; Meadows, SK; Russell, JL; Doan, P; Chi, J-T; Salter, AB; Lento, WE; Reya, T; Chao, NJ; Chute, JP
MLA Citation
Himburg, Heather A., et al. “Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells..” Nat Med, vol. 16, no. 4, Apr. 2010, pp. 475–82. Pubmed, doi:10.1038/nm.2119.
PMID
20305662
Source
pubmed
Published In
Nat Med
Volume
16
Issue
4
Publish Date
2010
Start Page
475
End Page
482
DOI
10.1038/nm.2119

Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.

Hematopoietic stem cells (HSCs) are enriched for aldehyde dehydrogenase (ALDH) activity and ALDH is a selectable marker for human HSCs. However, the function of ALDH in HSC biology is not well understood. We sought to determine the function of ALDH in regulating HSC fate. Pharmacologic inhibition of ALDH with diethylaminobenzaldehyde (DEAB) impeded the differentiation of murine CD34(-)c-kit(+)Sca-1(+)lineage(-) (34(-)KSL) HSCs in culture and facilitated a ninefold expansion of cells capable of radioprotecting lethally irradiated mice compared to input 34(-)KSL cells. Treatment of bone marrow (BM) 34(-)KSL cells with DEAB caused a fourfold increase in 4-week competitive repopulating units, verifying the amplification of short-term HSCs (ST-HSCs) in response to ALDH inhibition. Targeted siRNA of ALDH1a1 in BM HSCs caused a comparable expansion of radioprotective progenitor cells in culture compared to DEAB treatment, confirming that ALDH1a1 was the target of DEAB inhibition. The addition of all trans retinoic acid blocked DEAB-mediated expansion of ST-HSCs in culture, suggesting that ALDH1a1 regulates HSC differentiation via augmentation of retinoid signaling. Pharmacologic inhibition of ALDH has therapeutic potential as a means to amplify ST-HSCs for transplantation purposes.

Authors
Muramoto, GG; Russell, JL; Safi, R; Salter, AB; Himburg, HA; Daher, P; Meadows, SK; Doan, P; Storms, RW; Chao, NJ; McDonnell, DP; Chute, JP
MLA Citation
Muramoto, Garrett G., et al. “Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity..” Stem Cells, vol. 28, no. 3, Mar. 2010, pp. 523–34. Pubmed, doi:10.1002/stem.299.
PMID
20054864
Source
pubmed
Published In
Stem Cells
Volume
28
Issue
3
Publish Date
2010
Start Page
523
End Page
534
DOI
10.1002/stem.299

Advances in cord blood transplants in adults.

Umbilical cord blood is an acceptable source of hematopoietic stem cells for patients with malignant diseases but has limitations in its use. In this review, we will discuss these limitations and the recent advances in cord blood transplants that may enable cord blood to become more widely available as an alternative stem cell source for adults for the treatment of malignant diseases and for use in regenerative medicine.

Authors
Doan, PL; Chao, NJ
MLA Citation
Doan, Phuong L., and Nelson J. Chao. “Advances in cord blood transplants in adults..” F1000 Med Rep, vol. 2, Feb. 2010. Pubmed, doi:10.3410/M2-12.
PMID
20948874
Source
pubmed
Published In
F1000 Medicine Reports
Volume
2
Publish Date
2010
DOI
10.3410/M2-12

Long Term Survival Following High-dose Sequential Therapy with Autologous Hematopoietic Cell Rescue for Multiple Myeloma

High-dose therapy (HDT) with autologous hematopoietic cell rescue (AHCR) improves survival in patients with multiple myeloma, but is not curative due to a continuous risk of relapse. One approach to try to reduce relapse is to optimize the pretransplant therapy and preparative regimen. We investigated the outcome of sequential HDT with AHCR. Patients were initially treated with standard dose chemotherapy (primarily VAD) to maximum response. They then received cyclophosphamide 4 gm/m2 followed by G-CSF and peripheral blood hematopoietic cell collection by apheresis upon count recovery. They were then treated with etoposide 2 gm/m2 followed by G-CSF and apheresis upon count recovery. The transplant preparative regimen consisted of carmustine 500 mg/m2 on day -4 and melphalan 200 mg/m2 on day -2 followed by AHCR on day 0. Seventy-seven patients were enrolled between 1997 and 2001. Patients were eligible for enrollment if they had a confirmed diagnosis of multiple myeloma at the transplant center, had received multi-agent based chemotherapy for cytoreduction, and had no serious comorbidities. The patient population included 56% men with a median age at transplant of 54 years (range 39-68 years). Thirty-eight patients had IgG myeloma, 14 patients had IgA myeloma, 8 patients had light chain only disease, 4 patients had nonsecretory disease and subtype is unknown in six patients. The median progression-free survival was 3.9 years [CI 2.7-6.0 years] with a median overall survival of 9.5 years (CI 4.7-11 years). The median follow up of the 36 surviving patients is 8.43 years with a range of 4.71 to 11.09 years. One patient was lost to follow up. The Kaplan-Meir estimated progression-free survival at 10 years is 35% with overall survival of 45%. One patient developed secondary acute myeloid leukemia and one patient developed secondary myelodysplastic syndrome. High dose sequential therapy results in long term survival in a significant proportion of patients with multiple myeloma.

Authors
Doan, PL; Chute, JP; Gasparetto, C; Horwitz, M; Rizzieri, D; Smith, C; Sullivan, K; Edwards, J; Jacobson, R; Corbett, K; Chao, N; Long, G
MLA Citation
Doan, P. L., et al. Long Term Survival Following High-dose Sequential Therapy with Autologous Hematopoietic Cell Rescue for Multiple Myeloma. Vol. 16, no. 2, 2010, pp. S201–S201.
Source
manual
Volume
16
Issue
2
Publish Date
2010
Start Page
S201
End Page
S201

Colorectal Liver Metastases

Authors
Doan, PL; Vauthey, JN; Palavecino, M; Morse, MA
MLA Citation
Doan, P. L., et al. “Colorectal Liver Metastases.” Malignant Liver Tumors: Current and Emerging Therapies: Third Edition, 2009, pp. 342–46. Scopus, doi:10.1002/9781444317053.ch29.
Source
scopus
Publish Date
2009
Start Page
342
End Page
346
DOI
10.1002/9781444317053.ch29

Systemic Administration of Pleiotrophin Induces Hematopoietic Stem Cell Regeneration In Vivo

Authors
Himburg, HA; Daher, P; Meadows, SK; Russell, JL; Doan, P; Muramoto, G; Chao, NJ; Chute, J
MLA Citation
Himburg, Heather A., et al. “Systemic Administration of Pleiotrophin Induces Hematopoietic Stem Cell Regeneration In Vivo.” Blood, vol. 114, no. 22, AMER SOC HEMATOLOGY, 2009, pp. 602–602.
Source
wos
Published In
Blood
Volume
114
Issue
22
Publish Date
2009
Start Page
602
End Page
602

Deletion of Bak and Bax in Tie2+BM Hematopoietic Stem Cells Induces a B Cell Lymphoproliferative Disorder

Authors
Doan, PL; Russell, JL; Meadows, SK; Himburg, HA; Daher, P; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, Phuono L., et al. “Deletion of Bak and Bax in Tie2+BM Hematopoietic Stem Cells Induces a B Cell Lymphoproliferative Disorder.” Blood, vol. 114, no. 22, AMER SOC HEMATOLOGY, 2009, pp. 513–513.
Source
wos
Published In
Blood
Volume
114
Issue
22
Publish Date
2009
Start Page
513
End Page
513

Tie2+Bone Marrow Endothelial Cells Regulate Hematopoietic Reconstitution In Vivo

Authors
Doan, PL; Russell, JL; Meadows, SK; Himburg, HA; Daher, P; Chao, NJ; Kirsch, DG; Chute, JP
MLA Citation
Doan, Phuong L., et al. “Tie2+Bone Marrow Endothelial Cells Regulate Hematopoietic Reconstitution In Vivo.” Blood, vol. 114, no. 22, AMER SOC HEMATOLOGY, 2009, pp. 106–106.
Source
wos
Published In
Blood
Volume
114
Issue
22
Publish Date
2009
Start Page
106
End Page
106

The role of oral beclometasone dipropionate in the treatment of gastrointestinal Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation causes significant morbidity and mortality. An important site of GVHD is the gastrointestinal (GI) tract because development of acute GI GVHD is prognostic of overall survival. The standard of care to treat acute GI GVHD is systemic corticosteroids and immunosuppressants; however, the use of these therapies can cause life-threatening opportunistic infections. To limit the adverse effects of systemic immunosuppression, the topically active corticosteroid beclometasone dipropionate has been investigated in case studies and in randomized placebo-controlled trials for the treatment of acute GI GVHD. In this review, we appraise these studies with beclometasone dipropionate, and discuss future randomized studies to clarify the role of beclometasone dipropionate for the treatment and prevention of acute GVHD. At present, more data are required before the addition of beclometasone dipropionate to systemic corticosteroids for the treatment of acute GVHD can be considered the standard of care.

Authors
Doan, PL; Chao, NJ
MLA Citation
Doan, Phuong L., and Nelson J. Chao. “The role of oral beclometasone dipropionate in the treatment of gastrointestinal Graft-versus-Host Disease..” Drugs, vol. 69, no. 10, July 2009, pp. 1339–50. Pubmed, doi:10.2165/00003495-200969100-00004.
PMID
19583452
Source
pubmed
Published In
Drugs
Volume
69
Issue
10
Publish Date
2009
Start Page
1339
End Page
1350
DOI
10.2165/00003495-200969100-00004

Umbilical cord blood: biology and transplantation.

Umbilical cord blood transplantation is becoming an acceptable alternative source of hematopoietic stem cells for patients with malignant diseases. Cord blood differs from bone marrow and peripheral blood progenitors in its immune tolerance and kinetics of engraftment. In this article, we will review the biology of cord blood stem cells and clinical studies of cord blood transplants in pediatric and adult populations. We will also discuss potential uses of cord blood stem cells in regenerative medicine and novel methods for ex vivo expansion of hematopoietic stem cells. As we learn more about cord blood transplants, there is the potential to overcome the limitations of cord blood transplants so that they can become more widely available.

Authors
Doan, PL; Chao, NJ
MLA Citation
Doan, Phuong L., and Nelson J. Chao. “Umbilical cord blood: biology and transplantation..” Expert Rev Hematol, vol. 2, no. 2, Apr. 2009, pp. 197–208. Pubmed, doi:10.1586/ehm.09.9.
PMID
21083452
Source
pubmed
Published In
Expert Review of Hematology
Volume
2
Issue
2
Publish Date
2009
Start Page
197
End Page
208
DOI
10.1586/ehm.09.9

Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo.

Hematopoietic stem cells (HSCs) reside in association with bone marrow (BM) sinusoidal vessels in vivo, but the function of BM endothelial cells (ECs) in regulating hematopoiesis is unclear. We hypothesized that hematopoietic regeneration following injury is regulated by BM ECs. BALB/c mice were treated with total body irradiation (TBI) and then infused with C57Bl6-derived endothelial progenitor cells (EPCs) to augment endogenous BM EC activity. TBI caused pronounced disruption of the BM vasculature, BM hypocellularity, ablation of HSCs, and pancytopenia in control mice, whereas irradiated, EPC-treated mice displayed accelerated recovery of BM sinusoidal vessels, BM cellularity, peripheral blood white blood cells (WBCs), neutrophils, and platelets, and a 4.4-fold increase in BM HSCs. Systemic administration of anti-VE-cadherin antibody significantly delayed hematologic recovery in both EPC-treated mice and irradiated, non-EPC-treated mice compared with irradiated controls. These data demonstrate that allogeneic EPC infusions can augment hematopoiesis and suggest a relationship between BM microvascular recovery and hematopoietic reconstitution in vivo.

Authors
Salter, AB; Meadows, SK; Muramoto, GG; Himburg, H; Doan, P; Daher, P; Russell, L; Chen, B; Chao, NJ; Chute, JP
MLA Citation
Salter, Alice B., et al. “Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo..” Blood, vol. 113, no. 9, Feb. 2009, pp. 2104–07. Pubmed, doi:10.1182/blood-2008-06-162941.
PMID
19141867
Source
pubmed
Published In
Blood
Volume
113
Issue
9
Publish Date
2009
Start Page
2104
End Page
2107
DOI
10.1182/blood-2008-06-162941

Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture.

The retinoid X receptor (RXR) contributes to the regulation of diverse biological pathways via its role as a heterodimeric partner of several nuclear receptors. However, RXR has no established role in the regulation of hematopoietic stem cell (HSC) fate. In this study, we sought to determine whether direct modulation of RXR signaling could impact human HSC self-renewal or differentiation. Treatment of human CD34(+)CD38(-)lin(-) cells with LG1506, a selective RXR modulator, inhibited the differentiation of HSCs in culture and maintained long-term repopulating HSCs in culture that were otherwise lost in response to cytokine treatment. Further studies revealed that LG1506 had a distinct mechanism of action in that it facilitated the recruitment of corepressors to the retinoic acid receptor (RAR)/RXR complex at target gene promoters, suggesting that this molecule was functioning as an inverse agonist in the context of this heterodimer. Interestingly, using combinatorial peptide phage display, we identified unique surfaces presented on RXR when occupied by LG1506 and demonstrated that other modulators that exhibited these properties functioned similarly at both a mechanistic and biological level. These data indicate that the RAR/RXR heterodimer is a critical regulator of human HSC differentiation, and pharmacological modulation of RXR signaling prevents the loss of human HSCs that otherwise occurs in short-term culture.

Authors
Safi, R; Muramoto, GG; Salter, AB; Meadows, S; Himburg, H; Russell, L; Daher, P; Doan, P; Leibowitz, MD; Chao, NJ; McDonnell, DP; Chute, JP
MLA Citation
Safi, Rachid, et al. “Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture..” Mol Endocrinol, vol. 23, no. 2, Feb. 2009, pp. 188–201. Pubmed, doi:10.1210/me.2008-0121.
PMID
19106195
Source
pubmed
Published In
Molecular Endocrinology (Baltimore, Md.)
Volume
23
Issue
2
Publish Date
2009
Start Page
188
End Page
201
DOI
10.1210/me.2008-0121

The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC).

4595 Background: Radiologic procedures that involve embolizing branches of the hepatic artery lengthen survival for patients with unresectable HCC, but the benefit of administering intrahepatic arterial chemotherapy during the embolization procedure is uncertain. METHODS: A retrospective review of all patients with HCC and undergoing an embolization in the last 10 years and with 2 years of follow-up data was undertaken at two institutions to compare the survival and TTP of patients receiving TACE compared with TAE. Prognostic factors analyzed included age, gender, race, largest tumor size, number of tumors, macrovascular invasion, AFP, Child's class, and CLIP score. RESULTS: 122 pts with the following characteristics were included in the analysis: 71% Caucasian, 22% African American, 52% HCV+, 13% HBV+, 66% with cirrhosis, Child's A/B/C 70/25/5%, CLIP Score 0,1/2/>3 52/26/21%, 72% had either 1 or 2 tumors, 14% macrovascular invasion, 16% portal vein branch thrombosis, 20% extrahepatic disease. The procedure (TACE (51%, the majority receiving doxorubicin plus mitomycin C) and TAE (49%).was completed in one session in 87%. A subsequent embolization was performed in 37% for progression or new disease. The embolizing material was ethiodised oil in 39%, polyacrylamide/gelatin in 43%, and polyvinyl alcohol in 41%. The procedures were equally well tolerated. Although 37% of patients experienced an adverse event, readmission to the hospital was required in only 10%. One patient experienced fulminant hepatic failure. The median survival for TAE was 19.6 mo (95% CI 10.6-28.4) compared with 12.9mo (95% CI 7.0-19.5) for TACE (p=0.066). The TTP for TAE was 3.2mo (95% CI 2.1-6.0) compared with 4.1 mo (95% CI 2.1-5.6 for TACE (p=0.79). On multivariate analysis, the trend towards a difference in survival for TAE was eliminated and only CLIP score, AFP, and largest tumor remained as prognostic factors. CONCLUSIONS: This retropsective review suggests that adding chemotherapy to embolization does not improve survival compared with bland embolization in pts with HCC. Future efforts should focus on adjunctive therapies following the embolization to prevent progression or new primary tumors. No significant financial relationships to disclose.

Authors
Hanks, BA; Suhocki, PV; DeLong, DM; Doan, PL; Liu, E; Tsai, AL; Burke, CT; Bernard, SA; O'Neil, BH; Morse, MA
MLA Citation
Hanks, B. A., et al. “The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC)..” J Clin Oncol, vol. 26, no. 15_suppl, May 2008.
PMID
27948705
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
4595

Predictors of survival in patients with hepatocellular carcinoma treated with transarterial chemoembolization

Authors
Doan, PL; O'Neil, BH; Moore, DT; Bernard, SA
MLA Citation
Doan, P. L., et al. “Predictors of survival in patients with hepatocellular carcinoma treated with transarterial chemoembolization.” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 15522–15522. Crossref, doi:10.1200/jco.2008.26.15_suppl.15522.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
15522
End Page
15522
DOI
10.1200/jco.2008.26.15_suppl.15522

The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC)

Authors
Hanks, BA; Suhocki, PV; DeLong, DM; Doan, PL; Liu, E; Tsai, AL; Burke, CT; Bernard, SA; O’Neil, BH; Morse, MA
MLA Citation
Hanks, B. A., et al. “The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC).” Journal of Clinical Oncology, vol. 26, no. 15_suppl, American Society of Clinical Oncology (ASCO), May 2008, pp. 4595–4595. Crossref, doi:10.1200/jco.2008.26.15_suppl.4595.
Source
crossref
Published In
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
4595
End Page
4595
DOI
10.1200/jco.2008.26.15_suppl.4595

Abdominal varices caused by chronic Budd-Chiari syndrome.

Authors
Dellon, ES; Doan, PL; Batey, BM
MLA Citation
Dellon, Evan S., et al. “Abdominal varices caused by chronic Budd-Chiari syndrome..” Clin Gastroenterol Hepatol, vol. 4, no. 3, Mar. 2006. Pubmed, doi:10.1016/S1542-3565(05)00862-1.
PMID
16527683
Source
pubmed
Published In
Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association
Volume
4
Issue
3
Publish Date
2006
Start Page
xxiv
DOI
10.1016/S1542-3565(05)00862-1

Two types of recombination hotspots in bacteriophage T4: one requires DNA damage and a replication origin and the other does not.

Recombination hotspots have previously been discovered in bacteriophage T4 by two different approaches, marker rescue recombination from heavily damaged phage genomes and recombination during co-infection by two undamaged phage genomes. The phage replication origin ori(34) is located in a region that has a hotspot in both assays. To determine the relationship between the origin and the two kinds of hotspots, we generated phage carrying point mutations that should inactivate ori(34) but not affect the gene 34 reading frame (within which ori(34) is located). The mutations eliminated the function of the origin, as judged by both autonomous replication of plasmids during T4 infection and two-dimensional gel analysis of phage genomic replication intermediates. As expected from past studies, the ori(34) mutations also eliminated the hotspot for marker rescue recombination from UV-irradiated genomes. However, the origin mutations had no effect on the recombination hotspot that is observed with co-infecting undamaged phage genomes, demonstrating that some DNA sequence other than the origin is responsible for inflated recombination between undamaged genomes. The hotspots for marker rescue recombination may result from a replication fork restart process that acts upon origin-initiated replication forks that become blocked at nearby DNA damage. The two-dimensional gel analysis also revealed phage T4 replication intermediates not previously detected by this method, including origin theta forms.

Authors
Doan, PL; Belanger, KG; Kreuzer, KN
MLA Citation
Doan, P. L., et al. “Two types of recombination hotspots in bacteriophage T4: one requires DNA damage and a replication origin and the other does not..” Genetics, vol. 157, no. 3, Mar. 2001, pp. 1077–87.
PMID
11238396
Source
pubmed
Published In
Genetics
Volume
157
Issue
3
Publish Date
2001
Start Page
1077
End Page
1087
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Research Areas:

  • Antineoplastic Agents
  • Bone Marrow
  • Endothelial Cells
  • Epidermal Growth Factor
  • Gene Expression
  • Hematologic Neoplasms
  • Hematopoiesis
  • Hematopoietic Stem Cells
  • Radiation Injuries, Experimental
  • Radiation, Ionizing
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Epidermal Growth Factor
  • Regeneration
  • Stem Cell Niche