Publications by authors named "Brenda Nguyen"

12 Publications

  • Page 1 of 1

Preclinical Evaluation of a Single Intravenous Infusion of hUC-MSC (BX-U001) in Rheumatoid Arthritis.

Cell Transplant 2020 Jan-Dec;29:963689720965896

Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA.

Rheumatoid arthritis (RA) is an inflammatory disease of the joints, which causes severe pain and excessive systemic circulation of harmful inflammatory cytokines. Current treatments are limited, with some patients not responding well, and some experiencing severe and detrimental side effects. Mesenchymal stem cells (MSC) are cell-based therapeutics being evaluated as potent immunomodulators in RA and may provide relief to patients not responding well to drug-based treatments. We evaluated the safety and efficacy of BX-U001 human umbilical cord tissue-derived mesenchymal stem cells (hUC-MSC) to treat RA, in support of a successful investigational new drug application. A collagen-induced arthritis (CIA) mouse model of RA was established in DBA/1 J mice. Mice from the treatment assessment group were given a tail vein infusion of hUC-MSC 24 days after primary RA induction, while control assessment (CA) group mice were given cell-free carrier solution. All animals were evaluated daily for RA symptoms via clinical scoring, blood was taken periodically for cytokine analysis, and mice were dissected at end point for histological analysis. A linear mixed model was used to compare the rate of change among groups. The clinical scores of TA group were significantly reduced compared with CA group ( < 0.01), indicating therapeutic effects. The histological scores of the joints in TA group were significantly lower than those in the CA group ( < 0.05), but had no significant difference compared with Healthy groups ( > 0.05). The concentration of (interleukin) IL-6 in TA group was significantly reduced by 80.0% ( < 0.0001) 2 days after treatment and by 93.4% at the experimental endpoint compared with levels prior to hUC-MSC injection. A single intravenous infusion of hUC-MSC (2 × 10 cells/mouse), to CIA-induced DBA/1 J mice, resulted in significant alleviation of RA symptoms and may provide significant therapeutic benefits in humans.
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http://dx.doi.org/10.1177/0963689720965896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784581PMC
October 2020

TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Department of Surgery.

A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines, such as TNF-α. Previous studies have shown that an altered epigenetic program directs diabetic macrophages toward a proinflammatory phenotype, contributing to a sustained inflammatory phase. Males absent on the first (MOF) is a histone acetyltransferase (HAT) that has been shown be a coactivator of TNF-α signaling and promote NF-κB-mediated gene transcription in prostate cancer cell lines. Based on MOF's role in TNF-α/NF-κB-mediated gene expression, we hypothesized that MOF influences macrophage-mediated inflammation during wound repair. We used myeloid-specific Mof-knockout (Lyz2Cre Moffl/fl) and diet-induced obese (DIO) mice to determine the function of MOF in diabetic wound healing. MOF-deficient mice exhibited reduced inflammatory cytokine gene expression. Furthermore, we found that wound macrophages from DIO mice had elevated MOF levels and higher levels of acetylated histone H4K16, MOF's primary substrate of HAT activity, on the promoters of inflammatory genes. We further identified that MOF expression could be stimulated by TNF-α and that treatment with etanercept, an FDA-approved TNF-α inhibitor, reduced MOF levels and improved wound healing in DIO mice. This report is the first to our knowledge to define an important role for MOF in regulating macrophage-mediated inflammation in wound repair and identifies TNF-α inhibition as a potential therapy for the treatment of chronic inflammation in diabetic wounds.
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http://dx.doi.org/10.1172/jci.insight.132306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141388PMC
March 2020

IDO1 in cancer: a Gemini of immune checkpoints.

Cell Mol Immunol 2018 May 29;15(5):447-457. Epub 2018 Jan 29.

Department of Neurological Surgery, Northwestern University, Chicago, USA.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan (Trp) into downstream catabolites known as kynurenines. Coincidently, numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer. Preclinical studies have further introduced an interesting paradox: while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden, approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival. Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy, these data suggest that there is a more complex mechanism of action than previously appreciated. Similar to the dual faces of the astrological Gemini, we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism, as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects. The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration, but the lack of a universal prognostic significance among all cancer subtypes. Finally, ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients.
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http://dx.doi.org/10.1038/cmi.2017.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068130PMC
May 2018

Association between blood folate concentrations and depression in reproductive aged U.S. women, NHANES (2011-2012).

J Affect Disord 2017 12 17;223:209-217. Epub 2017 Jul 17.

Rollins School of Public Health of Emory University, Atlanta, GA, USA. Electronic address:

Background: Blood folate concentrations have been linked to an increased risk of depression in adults. Depression is particularly pronounced among women; however, the association between folate concentration and depression is not well-examined among women of reproductive age. The purpose of our study was to assess the association between low serum and red blood cell folate concentration and the risk of moderate to severe depression among non-pregnant women of reproductive age in the United States (U.S.).

Methods: We used data from nationally representative, population-based U.S. National Health and Nutrition Examination Survey (NHANES) (2011-2012) examining non-pregnant women of reproductive age (20-44 years). We compared serum and red blood cell (RBC) folate concentrations between women with and without self-reported depression based on Patient Health Questionnaire-9 (PHQ-9) scores, and examined the association between folate concentrations and depression using linear and logistic regression analysis.

Results: A total of 16.7% of eligible women in our study reported to have moderate to severe depression. The median serum folate concentrations for women with and without depression were 17.8ng/ml and 17.2ng/ml, respectively (P = <0.01). There was no statistical difference in median RBC folate concentrations between women with and without depression (P = 0.2). Serum folate concentration was weakly associated with an increased risk of moderate to severe depression among non-pregnant women of reproductive age, after adjusting for important demographic and life-style factors (aOR: 1.11; 95% CI: 1.01, 1.22). There was no interaction with race and ethnicity.

Limitations: Cross-sectional design.

Conclusions: Folate concentrations in the blood may partly explain the increased risk of moderate to severe depression among non-pregnant women of reproductive age in the U.S. Robust prospective studies are needed to confirm our findings.
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http://dx.doi.org/10.1016/j.jad.2017.07.019DOI Listing
December 2017

Targeted Disruption of Chlamydia trachomatis Invasion by in Trans Expression of Dominant Negative Tarp Effectors.

Front Cell Infect Microbiol 2016 23;6:84. Epub 2016 Aug 23.

Division of Immunology and Pathogenesis, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida Orlando, FL, USA.

Chlamydia trachomatis invasion of eukaryotic host cells is facilitated, in part, by the type III secreted effector protein, Tarp. The role of Tarp in chlamydiae entry of host cells is supported by molecular approaches that examined recombinant Tarp or Tarp effectors expressed within heterologous systems. A major limitation in the ability to study the contribution of Tarp to chlamydial invasion of host cells was the prior absence of genetic tools for chlamydiae. Based on our knowledge of Tarp domain structure and function along with the introduction of genetic approaches in C. trachomatis, we hypothesized that Tarp function could be disrupted in vivo by the introduction of dominant negative mutant alleles. We provide evidence that transformed C. trachomatis produced epitope tagged Tarp, which was secreted into the host cell during invasion. We examined the effects of domain specific Tarp mutations on chlamydial invasion and growth and demonstrate that C. trachomatis clones harboring engineered Tarp mutants lacking either the actin binding domain or the phosphorylation domain had reduced levels of invasion into host cells. These data provide the first in vivo evidence for the critical role of Tarp in C. trachomatis pathogenesis and indicate that chlamydial invasion of host cells can be attenuated via the introduction of engineered dominant negative type three effectors.
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http://dx.doi.org/10.3389/fcimb.2016.00084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993794PMC
September 2017

High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors.

Blood 2016 10 5;128(16):2055-2067. Epub 2016 Jul 5.

Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA.

Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance.
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http://dx.doi.org/10.1182/blood-2016-02-701805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073184PMC
October 2016

To Screen or not to Screen: Low Dose Computed Tomography in Comparison to Chest Radiography or Usual Care in Reducing Morbidity and Mortality from Lung Cancer.

Cureus 2016 Apr 27;8(4):e589. Epub 2016 Apr 27.

College of Medicine, University of Central Florida.

Lung cancer has the highest mortality rate of all cancers. This paper seeks to address the question: Can the mortality of lung cancer be decreased by screening with low-dose computerized tomography (LDCT) in higher risk patients compared to chest X-rays (CXR) or regular patient care? Currently, CXR screening is recommended for certain high-risk patients. Several recent trials have examined the effectiveness of LDCT versus chest radiography or usual care as a control. These trials include National Lung Screening Trial (NLST), Detection And screening of early lung cancer with Novel imaging TEchnology (DANTE), Lung Screening Study (LSS), Depiscan, Italian Lung (ITALUNG), and Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON study). NLST, the largest trial (n=53, 454), demonstrated a decrease in mortality from lung cancer in the LDCT group (RRR=20%, P=0.004). LSS demonstrated a greater sensitivity in detecting both early stage and any stage of lung cancer in comparison to traditional CXR. Although the DANTE trial yielded data consistent with findings in LSS, it also showed that via LDCT screening a greater proportion of patients were placed under unnecessary surgical procedures. The Depiscan trial yielded a high nodule detection rate at the cost of a high false-positive rate compared to CXR screening. The ITALUNG and NELSON trials demonstrated the early detection capabilities of LDCT for lung cancers compared to usual care without surveillance imaging. False-positive findings with unnecessary workup, intervention, and radiation exposure remain significant concerns for routine LDCT screening. However, current data suggests LDCT may provide a highly sensitive and specific means for detecting lung cancers and reducing mortality.
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http://dx.doi.org/10.7759/cureus.589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889453PMC
April 2016

Examining Equity Sensitivity: An Investigation Using the Big Five and HEXACO Models of Personality.

Front Psychol 2015 8;6:2000. Epub 2016 Jan 8.

Haskayne School of Business, University of Calgary Calgary, AB, Canada.

The construct of equity sensitivity describes an individual's preference about his/her desired input to outcome ratio. Individuals high on equity sensitivity tend to be more input oriented, and are often called "Benevolents." Individuals low on equity sensitivity are more outcome oriented, and are described as "Entitleds." Given that equity sensitivity has often been described as a trait, the purpose of the present study was to examine major personality correlates of equity sensitivity, so as to inform both the nature of equity sensitivity, and the potential processes through which certain broad personality traits may relate to outcomes. We examined the personality correlates of equity sensitivity across three studies (total N = 1170), two personality models (i.e., the Big Five and HEXACO), the two most common measures of equity sensitivity (i.e., the Equity Preference Questionnaire and Equity Sensitivity Inventory), and using both self and peer reports of personality (in Study 3). Although results varied somewhat across samples, the personality variables of Conscientiousness and Honesty-Humility, followed by Agreeableness, were the most robust predictors of equity sensitivity. Individuals higher on these traits were more likely to be Benevolents, whereas those lower on these traits were more likely to be Entitleds. Although some associations between Extraversion, Openness, and Neuroticism and equity sensitivity were observed, these were generally not robust. Overall, it appears that there are several prominent personality variables underlying equity sensitivity, and that the addition of the HEXACO model's dimension of Honesty-Humility substantially contributes to our understanding of equity sensitivity.
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http://dx.doi.org/10.3389/fpsyg.2015.02000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705277PMC
January 2016

Chlamydia trachomatis Tarp harbors distinct G and F actin binding domains that bundle actin filaments.

J Bacteriol 2013 Feb 30;195(4):708-16. Epub 2012 Nov 30.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.

All species of Chlamydia undergo a unique developmental cycle that transitions between extracellular and intracellular environments and requires the capacity to invade new cells for dissemination. A chlamydial protein called Tarp has been shown to nucleate actin in vitro and is implicated in bacterial entry into human cells. Colocalization studies of ectopically expressed enhanced green fluorescent protein (EGFP)-Tarp indicate that actin filament recruitment is restricted to the C-terminal half of the effector protein. Actin filaments are presumably associated with Tarp via an actin binding alpha helix that is also required for actin nucleation in vitro, but this has not been investigated. Tarp orthologs from C. pneumoniae, C. muridarum, and C. caviae harbor between 1 and 4 actin binding domains located in the C-terminal half of the protein, but C. trachomatis serovar L2 has only one characterized domain. In this work, we examined the effects of domain-specific mutations on actin filament colocalization with EGFP-Tarp. We now demonstrate that actin filament colocalization with Tarp is dependent on two novel F-actin binding domains that endow the Tarp effector with actin-bundling activity. Furthermore, Tarp-mediated actin bundling did not require actin nucleation, as the ability to bundle actin filaments was observed in mutant Tarp proteins deficient in actin nucleation. These data shed molecular insight on the complex cytoskeletal rearrangements required for C. trachomatis entry into host cells.
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http://dx.doi.org/10.1128/JB.01768-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562089PMC
February 2013

β-N-Acetylglucosamine (O-GlcNAc) is a novel regulator of mitosis-specific phosphorylations on histone H3.

J Biol Chem 2012 Apr 27;287(15):12195-203. Epub 2012 Feb 27.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030-3498, USA.

O-Linked β-N-acetylglucosamine, or O-GlcNAc, is a dynamic post-translational modification that cycles on and off serine and threonine residues of nucleocytoplasmic proteins. The O-GlcNAc modification shares a complex relationship with phosphorylation, as both modifications are capable of mutually inhibiting the occupation of each other on the same or nearby amino acid residue. In addition to diabetes, cancer, and neurodegenerative diseases, O-GlcNAc appears to play a significant role in cell growth and cell cycle progression, although the precise mechanisms are still not well understood. A recent study also found that all four core nucleosomal histones (H2A, H2B, H3, and H4) are modified with O-GlcNAc, although no specific sites on H3 were reported. Here, we describe that histone H3, a protein highly phosphorylated during mitosis, is modified with O-GlcNAc. Several biochemical assays were used to validate that H3 is modified with O-GlcNAc. Mass spectrometry analysis identified threonine 32 as a novel O-GlcNAc site. O-GlcNAc was detected at higher levels on H3 during interphase than mitosis, which inversely correlated with phosphorylation. Furthermore, increased O-GlcNAcylation was observed to reduce mitosis-specific phosphorylation at serine 10, serine 28, and threonine 32. Finally, inhibiting OGA, the enzyme responsible for removing O-GlcNAc, hindered the transition from G2 to M phase of the cell cycle, displaying a phenotype similar to preventing mitosis-specific phosphorylation on H3. Taken together, these data indicate that O-GlcNAcylation regulates mitosis-specific phosphorylations on H3, providing a mechanistic switch that orchestrates the G2-M transition of the cell cycle.
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http://dx.doi.org/10.1074/jbc.M111.315804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320971PMC
April 2012

A behavioral genetic study of the dark triad of personality and moral development.

Twin Res Hum Genet 2009 Apr;12(2):132-6

Department of Psychology, University of Western Ontario, Canada.

The present study is the first behavioral genetic investigation of relationships between the Dark Triad of personality--Machiavellianism, narcissism, and subclinical psychopathy--and moral development. Participants were 154 monozygotic twin pairs and 82 same-sex dizygotic twin pairs. Higher scores on Machiavellianism and psychopathy were positively correlated with low levels of moral development; high psychopathy scores also correlated negatively with high levels of moral development. Individual differences in lower levels of moral development were attributable to genetic and nonshared environmental factors but, very interestingly, individual differences in the highest levels of moral development showed no genetic basis but were entirely attributable to shared and nonshared environmental factors. Finally, correlations between the Dark Triad and moral development variables showed no genetic basis while correlations among the moral development variables were variously attributable to correlated genetic and correlated environmental factors.
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http://dx.doi.org/10.1375/twin.12.2.132DOI Listing
April 2009