Publications by authors named "Philip Bondzie"

11 Publications

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Prevention and treatment of malaria in pregnancy: what do pregnant women and health care workers in East India know and do about it?

Malar J 2018 May 18;17(1):207. Epub 2018 May 18.

Department of Global Health, Boston University School of Public Health, 801 Massachusetts Ave, Boston, MA, USA.

Background: Limited qualitative research has been performed in India to investigate views and behaviours of pregnant women regarding malaria despite the threat of malaria-related adverse maternal and neonatal outcomes. To address this gap, a comprehensive study on malaria prevention and treatment attitudes, knowledge and behaviour among pregnant women in India was conducted.

Methods: Pregnant women and healthcare workers (HCWs), encompassing clinic-based providers, traditional birth attendants, and auxiliary nurse-midwives were enrolled for in-depth interviews (IDIs) at 7 hospital sites and nearby communities in Jharkhand and Chhattisgarh States. Questions addressed health concerns and attitudes, knowledge and practices regarding malaria prevention and treatment; probing covered modern and traditional approaches. Data were analyzed using a thematic approach.

Results: A total of 83 pregnant women and 119 HCWs participated in 202 IDIs, 90 in Jharkhand and 112 in Chhattisgarh. A majority of Jharkhand respondents, but only one-fourth in Chhattisgarh, named malaria among top health issues for pregnant women. Just over half of pregnant women were willing to try new prevention methods (especially insecticide-treated bed nets), although cost-related barriers to such methods were stressed. Most respondents voiced concerns about malaria treatment during pregnancy, mainly citing potential harm to the baby. Most knew that mosquitoes transmitted malaria, but a substantial minority, including among HCWs, described incorrect transmission modes. Most knew a proven prevention method (usually bed nets or coils); a few knew other methods. A minority of pregnant women, but most HCWs, knew about malaria treatment, although some HCWs described unproven treatments. Most respondents described use of modern prevention methods in their communities, typically bed nets, although probing revealed irregular use. Half (especially in Jharkhand and particularly HCWs) described use of traditional prevention approaches such as burning leaves and rubbing oils on the body; traditional remedies for malaria treatment were common, and varied by site and population.

Conclusions: Understanding of malaria varied as a concern for pregnant women, continued use of unproven malaria prevention and treatment strategies was evident in this population in India. These results highlight the need to educate both pregnant women and HCWs about effective malaria methods to protect pregnant women and their babies from malaria.
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http://dx.doi.org/10.1186/s12936-018-2339-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960115PMC
May 2018

TMIGD1 acts as a tumor suppressor through regulation of p21Cip1/p27Kip1 in renal cancer.

Oncotarget 2018 Feb 26;9(11):9672-9684. Epub 2017 Dec 26.

Department of Pathology, Boston University School of Medicine, Boston, MA 02118, USA.

Renal cell carcinoma (RCC) is a high-risk metastasizing tumor with a poor prognosis and poorly understood mechanism. In this study, we demonstrate that transmembrane and immunoglobulin domain-containing 1 (TMIGD1) is a novel tumor suppressor that is highly expressed in normal renal tubular epithelial cells, but it is downregulated in human renal cancer. We have identified CCAAT/enhancer-binding proteinβ (C/EBPβ, also called LAP) as a key transcriptional regulator of TMIGD1, whose loss of expression is responsible for downregulation of TMIGD1 in RCC. Transcriptionally active C/EBPβ/LAP physically interacted with and increased TMIGD1 promoter activity and expression of TMIGD1. Re-introduction of TMIGD1 into renal tumor cells significantly inhibited tumor growth and metastatic behaviors such as morphogenic branching and cell migration. Restoring TMIGD1 expression in renal tumor cells stimulated phosphorylation of p38MAK, induced expression of p21CIP1 (cyclin-dependent kinase inhibitor 1), and p27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in regulation of the cell cycle. The present study identifies TMIGD1 as a novel candidate tumor suppressor gene and provides important insight into pathobiology of RCC that could lead to a better diagnosis and possible novel therapy for RCC.
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http://dx.doi.org/10.18632/oncotarget.23822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839393PMC
February 2018

MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth.

J Mol Cell Biol 2018 06;10(3):195-204

Department of Pathology, School of Medicine, Boston University Medical Campus, Boston, MA, USA.

Intrinsically disordered proteins (IDPs)/intrinsically unstructured proteins are characterized by the lack of fixed or stable tertiary structure, and are increasingly recognized as an important class of proteins with major roles in signal transduction and transcriptional regulation. In this study, we report the identification and functional characterization of a previously uncharacterized protein (UPF0258/KIAA1024), major intrinsically disordered Notch2-associated receptor 1 (MINAR1). While MINAR1 carries a single transmembrane domain and a short cytoplasmic domain, it has a large extracellular domain that shares no similarity with known protein sequences. Uncharacteristically, MINAR1 is a highly IDP with nearly 70% of its amino acids sequences unstructured. We demonstrate that MINAR1 physically interacts with Notch2 and its binding to Notch2 increases its stability and function. MINAR1 is widely expressed in various tissues including the epithelial cells of the breast and endothelial cells of blood vessels. MINAR1 plays a negative role in angiogenesis as it inhibits angiogenesis in cell culture and in mouse matrigel plug and zebrafish angiogenesis models. Furthermore, while MINAR1 is highly expressed in the normal human breast, its expression is significantly downregulated in advanced human breast cancer and its re-expression in breast cancer cells inhibited tumor growth. Our study demonstrates that MINAR1 is an IDP that negatively regulates angiogenesis and growth of breast cancer cells.
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http://dx.doi.org/10.1093/jmcb/mjy002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025234PMC
June 2018

Evaluation of Mental Disorders Using Proton Magnetic Resonance Spectroscopy in Dialysis and Predialysis Patients.

Kidney Blood Press Res 2017 21;42(4):686-696. Epub 2017 Nov 21.

Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background/aims: Psychological complications are prevalent in patients with chronic kidney disease (CKD). This study aimed to investigate mental disorders in stage 4-5 CKD patients, to detect metabolite concentrations in the brain by proton magnetic resonance spectroscopy (1H-MRS) and to compare the effects of different dialysis therapies on mental disorders in end-stage renal disease (ESRD).

Methods: The sample population was made up of predialysis (13), hemodialysis (HD) (13), and peritoneal dialysis (PD) patients (12). We collected the baseline data of patients' age, sex, hemoglobin (Hb) and parathyroid hormone(PTH) levels. The predialysis patients served as the control group. The psychological status of the three groups was assessed using three psychological scales. 1H-MRS was used to evaluate the relative metabolite concentrations in the bilateral amygdala, hippocampus and unilateral anterior cingulated cortex (ACC).

Results: The psychological status was better in HD patients than in predialysis and PD patients. 1H-MRS alterations were predominantly found in the ACC. Choline-containing compounds relative to creatine (Cho/Cr), myo-inositol relative to creatine (MI/Cr) and glutamate and glutamine relative to creatine (Glx/Cr) in the ACC were higher in HD patients. 1H-MRS results were correlated with the baseline data and the scores of psychological scales.

Conclusions: CKD patients showed different types of mental disorders as well as metabolite disturbances in the brain. The metabolite concentrations correlated with the psychological status which was better in HD than in predialytic and PD patients.
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http://dx.doi.org/10.1159/000484023DOI Listing
August 2018

IGPR-1 Is Required for Endothelial Cell-Cell Adhesion and Barrier Function.

J Mol Biol 2016 12 9;428(24 Pt B):5019-5033. Epub 2016 Nov 9.

Department of Pathology, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address:

Endothelial cell (EC) barrier function plays a prevalent regulatory mechanism for the integrity and homeostasis of blood vessels and modulates angiogenesis and immune responses. Cell adhesion molecules (CAMs) play a central role in the barrier function of ECs. Although Ig-containing and proline-rich receptor-1(IGPR-1) was recently identified as a novel CAM expressed in ECs, the molecular mechanisms underlying the function of IGPR-1 in ECs remain uncharacterized. In this report, we investigated the role of IGPR-1 in EC barrier function and the molecular mechanism of its activation in ECs. We demonstrate that IGPR-1 is localized to endothelial adherens junctions and, through trans-homophilic dimerization, regulates endothelial cell-cell adhesion and barrier function. Trans-homophilic dimerization of IGPR-1 stimulates the phosphorylation of serine 220 (Ser220), which is required for IGPR-1 to regulate endothelial barrier function and angiogenesis. Moreover, IGPR-1 chimera, which mimics the trans-homophilic dimerization of IGPR-1, induced a sustained phosphorylation of Ser220 upon stimulation with a ligand. Coordinated dimerization of IGPR-1 and its homophilic interaction modulates its adhesive function and Ser220 phosphorylation. This adhesive function of IGPR-1 contributes to the barrier function of ECs.
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http://dx.doi.org/10.1016/j.jmb.2016.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5138093PMC
December 2016

Non-muscle myosin-IIA is critical for podocyte f-actin organization, contractility, and attenuation of cell motility.

Cytoskeleton (Hoboken) 2016 Aug 21;73(8):377-95. Epub 2016 Jul 21.

Department of Pathology and Laboratory Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts.

Several glomerular pathologies resulting from podocyte injury are linked to genetic variation involving the MYH9 gene, which encodes the heavy chain of non-muscle myosin-IIA (NM-IIA). However, the functional role of NM-IIA has not been studied extensively in podocytes. We hypothesized that NM-IIA is critical for maintenance of podocyte structure and mechanical function. To test this hypothesis, we studied murine podocytes in vitro subjected to blebbistatin inhibition of NM-II activity, or RNA interference-mediated, isoform-specific ablation of Myh9 gene and protein (NM-IIA) or its paralog Myh10 gene and protein (NM-IIB). Using quantitative immunofluorescence microscopy, traction force microscopy, and attachment and "wound healing" assays, we found that NM-IIA ablation altered podocyte actin cytoskeletal structure and focal adhesion distribution, decreased cell attachment and contractility, and increased cell motility. Blebbistatin treatment had similar effects. NM-IIB ablation produced cells that exhibited poor attachment, but cytoskeletal structural organization, contractility and motility were maintained. These findings indicate that NM-IIA is essential for maintenance of podocyte cytoskeletal structure and mechanical function in vitro, and NM-IIB does not replace it in this role when NM-IIA expression is altered. We conclude that critical podocyte functions may be affected by MYH9 mutations or disease-associated haplotypes. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/cm.21313DOI Listing
August 2016

TMIGD1 is a novel adhesion molecule that protects epithelial cells from oxidative cell injury.

Am J Pathol 2015 Oct 2;185(10):2757-67. Epub 2015 Sep 2.

Department of Pathology, Boston University Medical Campus, Boston, Massachusetts; Department of Ophthalmology, School of Medicine, Boston University Medical Campus, Boston, Massachusetts. Electronic address:

Oxidative damage to renal tubular epithelial cells is a fundamental pathogenic mechanism implicated in both acute kidney injury and chronic kidney diseases. Because epithelial cell survival influences the outcome of acute kidney injury and chronic kidney diseases, identifying its molecular regulators could provide new insight into pathobiology and possible new therapeutic strategies for these diseases. We have identified transmembrane and immunoglobulin domain-containing 1 (TMIGD1) as a novel adhesion molecule, which is highly conserved in humans and other species. TMIGD1 is expressed in renal tubular epithelial cells and promotes cell survival. The extracellular domain of TMIGD1 contains two putative immunoglobulin domains and mediates self-dimerization. Our data suggest that TMIGD1 regulates transepithelial electric resistance and permeability of renal epithelial cells. TMIGD1 controls cell migration, cell morphology, and protects renal epithelial cells from oxidative- and nutrient-deprivation-induced cell injury. Hydrogen peroxide-induced oxidative cell injury downregulates TMIGD1 expression and targets it for ubiquitination. Moreover, TMIGD1 expression is significantly affected in both acute kidney injury and in deoxy-corticosterone acetate and sodium chloride (deoxy-corticosterone acetate salt)-induced chronic hypertensive kidney disease mouse models. Taken together, we have identified TMIGD1 as a novel cell adhesion molecule expressed in kidney epithelial cells that protects kidney epithelial cells from oxidative cell injury to promote cell survival.
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http://dx.doi.org/10.1016/j.ajpath.2015.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607757PMC
October 2015

New insights into glomerular parietal epithelial cell activation and its signaling pathways in glomerular diseases.

Biomed Res Int 2015 19;2015:318935. Epub 2015 Mar 19.

Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.

The glomerular parietal epithelial cells (PECs) have aroused an increasing attention recently. The proliferation of PECs is the main feature of crescentic glomerulonephritis; besides that, in the past decade, PEC activation has been identified in several types of noninflammatory glomerulonephropathies, such as focal segmental glomerulosclerosis, diabetic glomerulopathy, and membranous nephropathy. The pathogenesis of PEC activation is poorly understood; however, a few studies delicately elucidate the potential mechanisms and signaling pathways implicated in these processes. In this review we will focus on the latest observations and concepts about PEC activation in glomerular diseases and the newest identified signaling pathways in PEC activation.
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http://dx.doi.org/10.1155/2015/318935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383425PMC
December 2015

Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis.

Cell Stem Cell 2015 Jan 20;16(1):51-66. Epub 2014 Nov 20.

Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:

Mesenchymal stem cells (MSCs) reside in the perivascular niche of many organs, including kidney, lung, liver, and heart, although their roles in these tissues are poorly understood. Here, we demonstrate that Gli1 marks perivascular MSC-like cells that substantially contribute to organ fibrosis. In vitro, Gli1(+) cells express typical MSC markers, exhibit trilineage differentiation capacity, and possess colony-forming activity, despite constituting a small fraction of the platelet-derived growth factor-β (PDGFRβ)(+) cell population. Genetic lineage tracing analysis demonstrates that tissue-resident, but not circulating, Gli1(+) cells proliferate after kidney, lung, liver, or heart injury to generate myofibroblasts. Genetic ablation of these cells substantially ameliorates kidney and heart fibrosis and preserves ejection fraction in a model of induced heart failure. These findings implicate perivascular Gli1(+) MSC-like cells as a major cellular origin of organ fibrosis and demonstrate that these cells may be a relevant therapeutic target to prevent solid organ dysfunction after injury.
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http://dx.doi.org/10.1016/j.stem.2014.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289444PMC
January 2015

Correlation of chemokine receptor CXCR4 mRNA in primary cutaneous melanoma with established histopathologic prognosticators and the BRAF status.

Melanoma Res 2014 Dec;24(6):621-5

aDivision of Graduate Medical Sciences bSchool of Public Health cBoston University School of Medicine dDepartment of Pathology eDepartment of Dermatology, Dermatopathology Section, Boston University School of Medicine, Boston, Massachusetts, USA.

Dysregulation of the chemokine receptor CXCR4 is relevant in melanoma progression, and the CXCR4/CXCL12 axis has been shown to activate cell cycle progression and malignant cell migration through stimulation of the mitogen-activated protein kinase pathway. Studies ascertaining the potential utility of CXCR4 mRNA as a prognosticator in melanoma have focused mainly on metastatic melanoma with conflicting results. In the light of this, we sought to explore the potential relationship between CXCR4 mRNA expression with established histopathologic prognosticators and BRAF status in melanoma. Archived consecutive samples (n=107) of primary cutaneous melanoma were retrieved and assessed for the following: CXCR4 mRNA (semiquantitative RT-PCR) and BRAF exon 15 status (DNA Sanger sequencing). Statistical analyses included correlation between CXCR4 mRNA levels and established histopathologic prognosticators as well as the BRAF status using univariate and multiple linear methods. Multivariable analyses revealed a significant correlation between elevated CXCR4 mRNA (low ΔCt value) and the presence of BRAF mutation (P=0.02). Absence of a brisk host response was associated with elevated CXCR4 mRNA expression (P=0.04). CXCR4 mRNA was significantly lower in AJCC stage 2 compared with stage 1 after controlling for significant clinical prognosticators (P=0.02). The association between elevated CXCR4 mRNA and absence of a brisk host response suggests that CXCR4 may be involved in regulation of the host immune response in melanoma and is a molecule of potential utility as a biomarker for recruiting melanoma patients for immunotherapy. Higher CXCR4 mRNA in patients with a BRAF mutation suggests its utility as a putative therapeutic target.
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http://dx.doi.org/10.1097/CMR.0000000000000120DOI Listing
December 2014

Protein expression of the chemokine receptor CXCR4 and its ligand CXCL12 in primary cutaneous melanoma--biomarkers of potential utility?

Hum Pathol 2014 Oct 2;45(10):2094-100. Epub 2014 Jul 2.

Dermatopathology section, Department of Dermatology, Boston University School of Medicine, Boston, MA 02118. Electronic address:

Dysregulation of the CXCR4/CXCL12 axis, relevant in melanoma progression, activates cell cycle progression and migration via stimulation of the MAPK pathway. We sought to ascertain the cooperativity of the CXCR4/CXCL12 axis with established prognosticators and BRAF status in melanoma. Samples (n = 107) of primary cutaneous melanoma were assessed for protein expression of CXCR4 and CXCL12, and molecular analyses were performed to ascertain BRAF status. Univariate analyses of CXCR4 protein showed that the proportion of CXCR4 positives was greater in melanomas with absence of mitoses (P < .0001), absence of ulceration (P = .0008), and absence of regression (P = .02). Patients presenting at shallower stages (American Joint Committee on Cancer [AJCC] 1-2) exhibited a larger proportion of CXCR4 positives (76.9%, P < .0001 and 69.0%, P = .008), whereas those at deeper stages (AJCC 3-4) exhibited a larger proportion of negatives (75.0%, P = .004 and 66.7%, P = .22). In a multivariate analysis, lower odds of CXCR4 protein expression were associated with AJCC stage 3 (odds ratio [OR]=0.16, P = .01), AJCC stage 4 (OR=0.17, P = .04), and mitoses (OR=0.21, P = .01). Univariate analyses of CXCL12 protein showed that the proportion of CXCL12 negatives was significantly smaller in melanomas with depth of at least 1 mm, absence of ulceration, and absence of vascular invasion (P < .0001 for all). CXCR4 and CXCL12 appear to be biomarkers associated with established prognosticators of good and poor clinical outcome, respectively, in primary cutaneous melanoma. A BRAF mutation does not appear to be associated with CXCR4/CXCL12 axis upregulation in primary cutaneous melanoma.
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http://dx.doi.org/10.1016/j.humpath.2014.06.018DOI Listing
October 2014
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