Publications by authors named "Tuoen Liu"

15 Publications

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Corrigendum to "Haploinsufficiency of multiple del(5q) genes induce B cell abnormalities in mice" [Leuk. Res. 96C (2020) 106428].

Leuk Res 2021 Jan 4;100:106478. Epub 2020 Dec 4.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2020.106478DOI Listing
January 2021

Haploinsufficiency of multiple del(5q) genes induce B cell abnormalities in mice.

Leuk Res 2020 09 23;96:106428. Epub 2020 Jul 23.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, United States; Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2020.106428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768807PMC
September 2020

Iliac vein stenting guided by intravascular ultrasound without iodinated contrast medium.

Vasa 2021 Jan 19;50(1):68-73. Epub 2020 Jun 19.

Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, West Virginia, United States.

Iliac vein compression syndrome, also known as May-Thurner Syndrome, is a type of vein reflux disorders which is often ignored due to lack of efficient diagnostic methods. The traditional gold standard of diagnosis is venography, but this has been challenged and largely replaced by intravascular ultrasound (IVUS). Here we report a case that a patient suffered with iodine anaphylaxis was successfully performed iliac vein stenting guided by using IVUS alone. This case provides the evidence that IVUS can offer necessary information for physicians in the diagnosis and treatment of iliac vein compression. We also find that balloon dilatation notch cannot precisely reflect the whole lesion, indicating it may be unreliable for diagnosis. Differ from the commonly accepted opinion, we find that comparing to IVUS, the notch of balloon dilatation cannot completely reflect the extent of lesion narrowness. Thus, we think the notch should not be used as a reference for seriousness of the lesion, and the diagnosis of stenosis cannot be ruled out even if there is no presence of notch.
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http://dx.doi.org/10.1024/0301-1526/a000873DOI Listing
January 2021

Hypomethylating Agent Azacitidine Is Effective in Treating Brain Metastasis Triple-Negative Breast Cancer Through Regulation of DNA Methylation of Keratin 18 Gene.

Transl Oncol 2020 Jun 11;13(6):100775. Epub 2020 May 11.

Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, 400 Lee Street North, Lewisburg, WV. Electronic address:

Breast cancer patients presenting with symptomatic brain metastases have poor prognosis, and current chemotherapeutic agents are largely ineffective. In this study, we evaluated the hypomethylating agent azacitidine (AZA) for its potential as a novel therapeutic in preclinical models of brain metastasis of breast cancer. We used the parental triple-negative breast cancer MDA-MB-231 (231) cells and their brain colonizing counterpart (231Br) to ascertain phenotypic differences in response to AZA. We observed that 231Br cells have higher metastatic potential compared to 231 cells. With regard to therapeutic value, the AZA IC value in 231Br cells is significantly lower than that in parental cells (P < .01). AZA treatment increased apoptosis and inhibited the Wnt signaling transduction pathway, angiogenesis, and cell metastatic capacity to a significantly higher extent in the 231Br line. AZA treatment in mice with experimental brain metastases significantly reduced tumor burden (P = .0112) and increased survival (P = .0026) compared to vehicle. Lastly, we observed a decreased expression of keratin 18 (an epithelial maker) in 231Br cells due to hypermethylation, elucidating a potential mechanism of action of AZA in treating brain metastases from breast cancer.
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http://dx.doi.org/10.1016/j.tranon.2020.100775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225776PMC
June 2020

Fifteen-degree clavicular hook plate achieves better clinical outcomes in the treatment of acromioclavicular joint dislocation.

J Int Med Res 2018 Nov 9;46(11):4547-4559. Epub 2018 Aug 9.

1 Department of Orthopedic Surgery, The Third Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Objective: Clavicular hook plate application is one of the most commonly used treatment methods for acromioclavicular (AC) joint dislocation, although it may cause multiple postoperative complications. We modified the regularly used 0° hook plate to 15° and compared the clinical outcomes of these two hook plates for treatment of AC joint dislocation.

Methods: Forty-three patients with acute AC joint dislocation were randomly enrolled (0° hook plate, 20 patients; 15° hook plate, 23 patients). The American Shoulder and Elbow Surgeons (ASES) and visual analog scale for pain (VASP) scores were evaluated preoperatively and at 3 days and 1, 2, 3, and 6 months postoperatively and compared between the two groups.

Results: Compared with the preoperative scores, the 6-month postoperative ASES score gradually increased but the VASP score decreased in both groups. Furthermore, the ASES and VASP scores were significantly different between the two groups at every postoperative time point.

Conclusion: The 15° hook plate is superior to the 0° hook plate in reducing shoulder pain and improving postoperative recovery in the treatment of AC joint dislocation.

Level Of Evidence: Level III; Treatment study (retrospective comparative study).
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http://dx.doi.org/10.1177/0300060518786910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259358PMC
November 2018

Effect of cannulated screws with deep circumflex iliac artery-bone grafting in the treatment of femoral neck fracture in young adults.

Injury 2018 Aug 12;49(8):1587-1593. Epub 2018 Jun 12.

Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, WV, 24901, United States. Electronic address:

Objectives: Surgical treatment of femoral neck fracture in young adults is clinically challenging due to the high incidence of avascular necrosis of femoral head and fracture nonunion. The objective of this study is to evaluate the effectiveness of cannulated screws with deep circumflex iliac artery bone grafting (DCIABG) by comparing to the routinely used method in the treatment of femoral neck fracture in young adults.

Methods: From March 2006 to December 2012, a total of 185 patients with femoral neck fracture were admitted to the hospital for internal fixation surgery, 103 patients (61 males and 42 females, mean age of 39.1 years) were treated with three cannulated screws with DCIABG (group A), and 82 patients (49 males and 33 females, mean age of 35.5 years) were treated with three cannulated screws without DCIABG (group B).

Results: All patients were followed up for at least 24 months after the surgery. The patients in group A had a significantly higher Harris Hip Score (p < 0.001), shorter fracture healing time (p < 0.001), lower occurrence rate of avascular necrosis of femoral head (p = 0.008) and fracture nonunion (p = 0.012) compared to the patients in group B. However, the operation time and intraoperative blood loss were significantly lower in patients in group B than those in group A (p < 0.001).

Conclusions: Cannulated screws with DCIABG significantly reduced femoral head osteonecrosis and fracture nonunion. Therefore, it is a feasible and effective method in the treatment of young adult patients with femoral neck fracture.
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http://dx.doi.org/10.1016/j.injury.2018.06.014DOI Listing
August 2018

Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells.

PLoS One 2017 8;12(2):e0170470. Epub 2017 Feb 8.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, United States of America.

Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170470PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298293PMC
August 2017

Heat Shock Proteins and Cancer.

Trends Pharmacol Sci 2017 03 22;38(3):226-256. Epub 2016 Dec 22.

Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China. Electronic address:

Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation whose expression is induced by heat shock or other stressors. The major groups are classified based on their molecular weights and include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSPs. HSPs play a significant role in cellular proliferation, differentiation, and carcinogenesis. In this article we comprehensively review the roles of major HSPs in cancer biology and pharmacology. HSPs are thought to play significant roles in the molecular mechanisms leading to cancer development and metastasis. HSPs may also have potential clinical uses as biomarkers for cancer diagnosis, for assessing disease progression, or as therapeutic targets for cancer therapy.
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http://dx.doi.org/10.1016/j.tips.2016.11.009DOI Listing
March 2017

Tubular Overexpression of Angiopoietin-1 Attenuates Renal Fibrosis.

PLoS One 2016 25;11(7):e0158908. Epub 2016 Jul 25.

Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.

Emerging evidence has highlighted the pivotal role of microvasculature injury in the development and progression of renal fibrosis. Angiopoietin-1 (Ang-1) is a secreted vascular growth factor that binds to the endothelial-specific Tie2 receptor. Ang-1/Tie2 signaling is critical for regulating blood vessel development and modulating vascular response after injury, but is dispensable in mature, quiescent vessels. Although dysregulation of vascular endothelial growth factor (VEGF) signaling has been well studied in renal pathologies, much less is known about the role of the Ang-1/Tie2 pathway in renal interstitial fibrosis. Previous studies have shown contradicting effects of overexpressing Ang-1 systemically on renal tubulointerstitial fibrosis when different engineered forms of Ang-1 are used. Here, we investigated the impact of site-directed expression of native Ang-1 on the renal fibrogenic process and peritubular capillary network by exploiting a conditional transgenic mouse system [Pax8-rtTA/(TetO)7 Ang-1] that allows increased tubular Ang-1 production in adult mice. Using a murine unilateral ureteral obstruction (UUO) fibrosis model, we demonstrate that targeted Ang-1 overexpression attenuates myofibroblast activation and interstitial collagen I accumulation, inhibits the upregulation of transforming growth factor β1 and subsequent phosphorylation of Smad 2/3, dampens renal inflammation, and stimulates the growth of peritubular capillaries in the obstructed kidney. Our results suggest that Ang-1 is a potential therapeutic agent for targeting microvasculature injury in renal fibrosis without compromising the physiologically normal vasculature in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959721PMC
July 2017

Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo.

Cancer Cell 2015 May;27(5):631-43

Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA. Electronic address:

Heterozygous somatic mutations in the spliceosome gene U2AF1 occur in ∼ 11% of patients with myelodysplastic syndromes (MDS), the most common adult myeloid malignancy. It is unclear how these mutations contribute to disease. We examined in vivo hematopoietic consequences of the most common U2AF1 mutation using a doxycycline-inducible transgenic mouse model. Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq). Integration with human RNA-seq datasets determined that common mutant U2AF1-induced splicing alterations are enriched in RNA processing genes, ribosomal genes, and recurrently mutated MDS and acute myeloid leukemia-associated genes. These findings support the hypothesis that mutant U2AF1 alters downstream gene isoform expression, thereby contributing to abnormal hematopoiesis in patients with MDS.
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http://dx.doi.org/10.1016/j.ccell.2015.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430854PMC
May 2015

Reduced levels of Hspa9 attenuate Stat5 activation in mouse B cells.

Exp Hematol 2015 Apr 27;43(4):319-30.e10. Epub 2014 Dec 27.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

HSPA9 is located on chromosome 5q31.2 in humans, a region that is commonly deleted in patients with myeloid malignancies [del(5q)], including myelodysplastic syndrome (MDS). HSPA9 expression is reduced by 50% in patients with del(5q)-associated MDS, consistent with haploinsufficient levels. Zebrafish mutants and knockdown studies in human and mouse cells have implicated a role for HSPA9 in hematopoiesis. To comprehensively evaluate the effects of Hspa9 haploinsufficiency on hematopoiesis, we generated an Hspa9 knockout mouse model. Although homozygous knockout of Hspa9 is embryonically lethal, mice with heterozygous deletion of Hspa9 (Hspa9(+/-)) are viable and have a 50% reduction in Hspa9 expression. Hspa9(+/-) mice have normal basal hematopoiesis and do not develop MDS. However, Hspa9(+/-) mice have a cell-intrinsic reduction in bone marrow colony-forming unit-PreB colony formation without alterations in the number of B-cell progenitors in vivo, consistent with a functional defect in Hspa9(+/-) B-cell progenitors. We further reduced Hspa9 expression (<50%) using RNA interference and observed reduced B-cell progenitors in vivo, indicating that appropriate levels (≥50%) of Hspa9 are required for normal B lymphopoiesis in vivo. Knockdown of Hspa9 in an interleukin 7 (IL-7)-dependent mouse B-cell line reduced signal transducer and activator of transcription 5 (Stat5) phosphorylation following IL-7 receptor stimulation, supporting a role for Hspa9 in Stat5 signaling in B cells. Collectively, these data imply a role for Hspa9 in B lymphopoiesis and Stat5 activation downstream of IL-7 signaling.
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http://dx.doi.org/10.1016/j.exphem.2014.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375022PMC
April 2015

Tyrosine phosphorylation of HSC70 and its interaction with RFC mediates methotrexate resistance in murine L1210 leukemia cells.

Cancer Lett 2015 Feb 20;357(1):231-241. Epub 2014 Nov 20.

Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello, ID, United States; The ISU Biomedical Research Institute, Idaho State University, Pocatello, ID, United States. Electronic address:

We previously identified and characterized a 66-68 kDa membrane-associated, tyrosine phosphorylated protein in murine leukemia L1210 cells as HSC70 which is a methotrexate (MTX)-binding protein. In order to further characterize the functional role of HSC70 in regulating MTX resistance in L1210 cells, we first showed that HSC70 colocalizes and interacts with reduced folate carrier (RFC) in L1210 cells by confocal laser scanning microscopy and Duolink in situ proximity ligation assay. The tyrosine phosphorylation status of HSC70 found in the membrane fraction was different from the parental L1210/0 and cisplatin (CDDP)-MTX cross resistant L1210/DDP cells. In MTX-binding assays, HSC70 from L1210/DDP cells showed less affinity for MTX-agarose beads than that of L1210/0 cells. In addition, genistein (a tyrosine phosphorylation inhibitor) significantly enhanced the resistance of L1210/0 cells to MTX. Moreover, site-directed mutation studies indicated the importance of tyrosine phosphorylation of HSC70 in regulating its binding to MTX. These findings suggest that tyrosine phosphorylation of HSC70 regulates the transportation of MTX into the cells via the HSC70-RFC system and contributes to MTX resistance in L1210 cells.
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http://dx.doi.org/10.1016/j.canlet.2014.11.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785865PMC
February 2015

Interleukin-6 and JAK2/STAT3 signaling mediate the reversion of dexamethasone resistance after dexamethasone withdrawal in 7TD1 multiple myeloma cells.

Leuk Res 2013 Oct 18;37(10):1322-8. Epub 2013 Jul 18.

Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.

We previously reported the establishment and characteristics of a DXM-resistant cell line (7TD1-DXM) generated from the IL6-dependent mouse B cell hybridoma, 7TD1 cell line. After withdrawing DXM from 7TD1-DXM cells over 90 days, DXM significantly inhibited the cell growth and induced apoptosis in the cells (7TD1-WD) compared with 7TD1-DXM cells. Additionally, IL-6 reversed while IL-6 antibody and AG490 enhanced the effects of growth inhibition and apoptosis induced by DXM in 7TD1-WD cells. Our study demonstrates that 7TD1-DXM cells become resensitized to DXM after DXM withdrawal, and IL-6 and JAK2/STAT3 pathways may regulate the phenomenon.
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http://dx.doi.org/10.1016/j.leukres.2013.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769515PMC
October 2013

Identification and characterization of a 66-68-kDa protein as a methotrexate-binding protein in murine leukemia L1210 cells.

Cell Stress Chaperones 2013 Mar 23;18(2):223-34. Epub 2012 Oct 23.

Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

We previously observed an unidentified, tyrosine-phosphorylated, membrane-associated, 66-68-kDa protein which was present in the L1210 murine leukemia cells but not present, at least in the tyrosine-phosphorylated form, in cisplatin-methotrexate (CDDP-MTX) cross-resistant L1210/DDP cells. We purified and characterized this 66-68-kDa protein by affinity chromatography purification using its two identified properties, tyrosine phosphorylation and MTX-binding, and yielded a single band of 66-68 kDa. The purified protein was subjected to trypsin digestion and the isolated peptide fragments were sequenced and yielded two partial peptide sequences: VEIIANDQ and VTNAVVTVPAYFNDSQRQA. The two peptide sequences were used to search for the mouse genome at the national center for biotechnology information (NCBI) database for Open Reading Frame Sequence (ORFs) containing these peptides using the TBLASTN function. A single gene was identified containing both sequences, the HSPa8 gene, which codes for the heat shock family protein, HSC70. We further demonstrated that HSC70 is a MTX-binding protein using a binding assay with MTX-agarose beads followed by Western blotting. The HSC70 also existed in various cancer cell lines and showed binding to MTX. Additionally, the HSC70 protein, cloned from the L1210 murine leukemia cells, was expressed and purified from E. coli cells using a polyhistidine-tag purification system and it also showed the binding properties with MTX. DnaK, the HSC70 homologue in E. coli, also binds to MTX. By using the purified truncated HSC70 domains, we identified the adenosine triphosphatase (ATPase) domain of HSC70 that can bind to MTX. Thus, we have tentatively characterized a new, novel property of HSC70 as a MTX-binding protein.
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http://dx.doi.org/10.1007/s12192-012-0376-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581622PMC
March 2013

Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential.

Pharmacol Ther 2012 Dec 29;136(3):354-74. Epub 2012 Aug 29.

Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.

Heat shock cognate protein 70 (HSC70) is a constitutively expressed molecular chaperone which belongs to the heat shock protein 70 (HSP70) family. HSC70 shares some of the structural and functional similarity with HSP70. HSC70 also has different properties compared with HSP70 and other heat shock family members. HSC70 performs its full functions by the cooperation of co-chaperones. It interacts with many other molecules as well and regulates various cellular functions. It is also involved in various diseases and may become a biomarker for diagnosis and potential therapeutic targets for design, discovery, and development of novel drugs to treat various diseases. In this article, we provide a comprehensive review on HSC70 from the literatures including the basic general information such as classification, structure and cellular location, genetics and function, as well as its protein association and interaction with other proteins. In addition, we also discussed the relationship of HSC70 and related clinical diseases such as cancer, cardiovascular, neurological, hepatic and many other diseases and possible therapeutic potential and highlight the progress and prospects of research in this field. Understanding the functions of HSC70 and its interaction with other molecules will help us to reveal other novel properties of this protein. Scientists may be able to utilize this protein as a biomarker and therapeutic target to make significant advancement in scientific research and clinical setting in the future.
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http://dx.doi.org/10.1016/j.pharmthera.2012.08.014DOI Listing
December 2012