Publications by authors named "Bushra Rahman"

29 Publications

  • Page 1 of 1

Comparison of the safety and efficacy of dexmedetomidine with midazolam for the management of paediatric dental patients: A systematic review.

J Indian Soc Pedod Prev Dent 2021 Jul-Sep;39(3):233-239

Department of Paediatric and Preventive Dentistry, I.T.S Dental College, Hospital and Research Centre, Greater Noida, Uttar Pradesh, India.

Background: Pain, fear, and anxiety have long been associated with pediatric dentistry. A child's cooperation with a dental.procedure.usually requires various behavioral management strategies conveyed by the entire dental team. The use of sedatives in dental clinics for providing analgesia and anxiolysis allows the patient to respond appropriately to verbal commands and light tactile stimulation., thus making dental treatment more patient friendly and effective.

Aim: The aim of this study was to compare the safety and efficacy of dexmedetomidine versus midazolam for the management of pediatric patients in the dental clinic.

Materials And Methods: This systematic review was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Six articles were selected for this systematic review. Of them, only in four articles, homogeneous data were available which were subjected to meta-analysis.

Results: When compared with midazolam, premedication with dexmedetomidine resulted in much lower incidence of emergence delirium (odds ratio = 0.07, 95% confidence interval: 0.01-0.54, P = 0.01). No significant difference was observed with respect to satisfactory behavior of the child, successful parental separation, and satisfactory mask acceptance following sedation.

Conclusion: Both dexmedetomidine and midazolam are equally effective for the management of pediatric patients in the dental clinic. In addition, dexmedetomidine premedication is associated with lower incidence of emergence delirium and has a better margin of safety.
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http://dx.doi.org/10.4103/jisppd.jisppd_517_20DOI Listing
November 2021

Impact of COVID-19 on presentation, staging, and treatment of head and neck mucosal squamous cell carcinoma.

Am J Otolaryngol 2021 Oct 8;43(1):103263. Epub 2021 Oct 8.

Department of Otolaryngology Head and Neck Surgery, Vanderbilt University Medical Center, 7th floor 1215 21st Ave S, Nashville, TN 37232, USA.

Objectives: During the COVID-19 pandemic, maintenance of safe and timely oncologic care has been challenging. The goal of this study is to compare presenting symptoms, staging, and treatment of head and neck mucosal squamous cell carcinoma during the pandemic with an analogous timeframe one year prior.

Materials And Methods: Retrospective cohort study at a single tertiary academic center of new adult patients evaluated in a head and neck surgical oncology clinic from March -July 2019 (pre-pandemic control) and March - July 2020 (COVID-19 pandemic).

Results: During the pandemic, the proportion of patients with newly diagnosed malignancies increased by 5%, while the overall number of new patients decreased (n = 575) compared to the control year (n = 776). For patients with mucosal squamous cell carcinoma (SCC), median time from referral to initial clinic visit decreased from 11 days (2019) to 8 days (2020) (p = 0.0031). There was no significant difference in total number (p = 0.914) or duration (p = 0.872) of symptoms. During the pandemic, patients were more likely to present with regional nodal metastases (adjusted odds ratio (OR) 2.846, 95% CI 1.072-3.219, p = 0.028) and more advanced clinical nodal (N) staging (p = 0.011). No significant difference was seen for clinical tumor (T) (p = 0.502) or metastasis (M) staging (p = 0.278). No significant difference in pathologic T (p = 0.665), or N staging (p = 0.907) was found between the two periods.

Conclusion: Head and neck mucosal SCC patients presented with more advanced clinical nodal disease during the early months of the COVID-19 pandemic despite no change in presenting symptoms.
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http://dx.doi.org/10.1016/j.amjoto.2021.103263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500684PMC
October 2021

Phosphorylation of slit diaphragm proteins NEPHRIN and NEPH1 upon binding of HGF promotes podocyte repair.

J Biol Chem 2021 09 13;297(3):101079. Epub 2021 Aug 13.

Division of Kidney, Urologic and Hematologic Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Phosphorylation (activation) and dephosphorylation (deactivation) of the slit diaphragm proteins NEPHRIN and NEPH1 are critical for maintaining the kidney epithelial podocyte actin cytoskeleton and, therefore, proper glomerular filtration. However, the mechanisms underlying these events remain largely unknown. Here we show that NEPHRIN and NEPH1 are novel receptor proteins for hepatocyte growth factor (HGF) and can be phosphorylated independently of the mesenchymal epithelial transition receptor in a ligand-dependent fashion through engagement of their extracellular domains by HGF. Furthermore, we demonstrate SH2 domain-containing protein tyrosine phosphatase-2-dependent dephosphorylation of these proteins. To establish HGF as a ligand, purified baculovirus-expressed NEPHRIN and NEPH1 recombinant proteins were used in surface plasma resonance binding experiments. We report high-affinity interactions of NEPHRIN and NEPH1 with HGF, although NEPHRIN binding was 20-fold higher than that of NEPH1. In addition, using molecular modeling we constructed peptides that were used to map specific HGF-binding regions in the extracellular domains of NEPHRIN and NEPH1. Finally, using an in vitro model of cultured podocytes and an ex vivo model of Drosophila nephrocytes, as well as chemically induced injury models, we demonstrated that HGF-induced phosphorylation of NEPHRIN and NEPH1 is centrally involved in podocyte repair. Taken together, this is the first study demonstrating a receptor-based function for NEPHRIN and NEPH1. This has important biological and clinical implications for the repair of injured podocytes and the maintenance of podocyte integrity.
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http://dx.doi.org/10.1016/j.jbc.2021.101079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429977PMC
September 2021

Comparative Evaluation of Indirect Pulp Therapy in Young Permanent Teeth using Biodentine and Theracal: A Randomized Clinical Trial.

J Clin Pediatr Dent 2021 Jul;45(3):158-164

Objective: In a tooth with deep dentinal caries; judicious removal of infected dentin and isolating affected dentin from oral fluids with suitable biocompatible material is called indirect pulp therapy (IPT). This randomized clinical trial was done to evaluate and compare the efficacy of Biodentine, Theracal LC and. Dycal as an indirect pulp capping agent in young permanent teeth.

Study Design: IPT was performed in 60 young permanent molars with caries approaching pulp in 55 healthy children using Biodentine, Theracal and Dycal. A 2-3mm layer of GIC was placed over the intervening material followed by restoration of cavity with composite. Clinical and radiographic examinations were conducted at 3 weeks, 3 months, 6 months,12 months, 18 months and 24 months. The data was compared using chi-square test at a significance level of 0.05.

Results: By end of 24 months ,54 teeth presented for follow up with overall success rate of 100% in Theracal, 94.44% in Biodentine, and 77.78% in Dycal. Overall success of Theracal was statistically significant in comparison to Biodentine and Dycal at 24 months follow up (p= 0.03) Conclusions: Radiographic and clinical outcomes of Theracal and Biodentine suggest their use as an alternative material for IPT in young permanent molars with higher success.
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http://dx.doi.org/10.17796/1053-4625-45.3.3DOI Listing
July 2021

Loss of Motor Protein MYO1C Causes Rhodopsin Mislocalization and Results in Impaired Visual Function.

Cells 2021 05 26;10(6). Epub 2021 May 26.

Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

Unconventional myosins, linked to deafness, are also proposed to play a role in retinal cell physiology. However, their direct role in photoreceptor function remains unclear. We demonstrate that systemic loss of the unconventional myosin MYO1C in mice, specifically causes rhodopsin mislocalization, leading to impaired visual function. Electroretinogram analysis of knockout (-KO) mice showed a progressive loss of photoreceptor function. Immunohistochemistry and binding assays demonstrated MYO1C localization to photoreceptor inner and outer segments (OS) and identified a direct interaction of rhodopsin with MYO1C. In -KO retinas, rhodopsin mislocalized to rod inner segments (IS) and cell bodies, while cone opsins in OS showed punctate staining. In aged mice, the histological and ultrastructural examination of the phenotype of -KO retinas showed progressively shorter photoreceptor OS. These results demonstrate that MYO1C is important for rhodopsin localization to the photoreceptor OS, and for normal visual function.
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http://dx.doi.org/10.3390/cells10061322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229726PMC
May 2021

Targeting myosin 1c inhibits murine hepatic fibrogenesis.

Am J Physiol Gastrointest Liver Physiol 2021 06 28;320(6):G1044-G1053. Epub 2021 Apr 28.

Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina.

Myosin 1c (Myo1c) is an unconventional myosin that modulates signaling pathways involved in tissue injury and repair. In this study, we observed that Myo1c expression is significantly upregulated in human chronic liver disease such as nonalcoholic steatohepatitis (NASH) and in animal models of liver fibrosis. High throughput data from the GEO-database identified similar Myo1c upregulation in mice and human liver fibrosis. Notably, transforming growth factor-β1 (TGF-β1) stimulation to hepatic stellate cells (HSCs), the liver pericyte and key cell type responsible for the deposition of extracellular matrix, upregulates Myo1c expression, whereas genetic depletion or pharmacological inhibition of Myo1c blunted TGF-β-induced fibrogenic responses, resulting in repression of α-smooth muscle actin (α-SMA) and collagen type I α 1 chain (Col1α1) mRNA. Myo1c deletion also decreased fibrogenic processes such as cell proliferation, wound healing response, and contractility when compared with vehicle-treated HSCs. Importantly, phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) and mothers against decapentaplegic homolog 3 (SMAD3) were significantly blunted upon Myo1c inhibition in GRX cells as well as Myo1c knockout (Myo1c-KO) mouse embryonic fibroblasts (MEFs) upon TGF-β stimulation. Using the genetic Myo1c-KO mice, we confirmed that Myo1c is critical for fibrogenesis, as Myo1c-KO mice were resistant to carbon tetrachloride (CCl4)-induced liver fibrosis. Histological and immunostaining analysis of liver sections showed that deposition of collagen fibers and α-SMA expression were significantly reduced in Myo1c-KO mice upon liver injury. Collectively, these results demonstrate that Myo1c mediates hepatic fibrogenesis by modulating TGF-β signaling and suggest that inhibiting this process may have clinical application in treating liver fibrosis. The incidences of liver fibrosis are growing at a rapid pace and have become one of the leading causes of end-stage liver disease. Although TGF-β1 is known to play a prominent role in transforming cells to produce excessive extracellular matrix that lead to hepatic fibrosis, the therapies targeting TGF-β1 have achieved very limited clinical impact. This study highlights motor protein myosin-1c-mediated mechanisms that serve as novel regulators of TGF-β1 signaling and fibrosis.
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http://dx.doi.org/10.1152/ajpgi.00105.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285590PMC
June 2021

Repurposing of a Thromboxane Receptor Inhibitor Based on a Novel Role in Metastasis Identified by Phenome-Wide Association Study.

Mol Cancer Ther 2020 12 8;19(12):2454-2464. Epub 2020 Oct 8.

Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.

Although new drug discoveries are revolutionizing cancer treatments, repurposing existing drugs would accelerate the timeline and lower the cost for bringing treatments to cancer patients. Our goal was to repurpose CPI211, a potent and selective antagonist of the thromboxane A-prostanoid receptor (TPr), a G-protein-coupled receptor that regulates coagulation, blood pressure, and cardiovascular homeostasis. To identify potential new clinical indications for CPI211, we performed a phenome-wide association study (PheWAS) of the gene encoding TPr, , using robust deidentified health records and matched genomic data from more than 29,000 patients. Specifically, PheWAS was used to identify clinical manifestations correlating with a single-nucleotide polymorphism (rs200445019), which generates a T399A substitution within TPr that enhances TPr signaling. Previous studies have correlated 200445019 with chronic venous hypertension, which was recapitulated by this PheWAS analysis. Unexpectedly, PheWAS uncovered an rs200445019 correlation with cancer metastasis across several cancer types. When tested in several mouse models of metastasis, TPr inhibition using CPI211 potently blocked spontaneous metastasis from primary tumors, without affecting tumor cell proliferation, motility, or tumor growth. Further, metastasis following intravenous tumor cell delivery was blocked in mice treated with CPI211. Interestingly, TPr signaling in vascular endothelial cells induced VE-cadherin internalization, diminished endothelial barrier function, and enhanced transendothelial migration by tumor cells, phenotypes that were decreased by CPI211. These studies provide evidence that TPr signaling promotes cancer metastasis, supporting the study of TPr inhibitors as antimetastatic agents and highlighting the use of PheWAS as an approach to accelerate drug repurposing.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-1106DOI Listing
December 2020

Oral submucous fibrosis and its impact on psychological stress: a case-control study.

Psychol Health Med 2020 Sep 29:1-11. Epub 2020 Sep 29.

Pediatrics and Preventive Dentistry, ITS Dental College, Greater Noida, India.

Our aim was to evaluate the impact of OSF on psychological stress. Ninety OSF cases and age and sex-matched controls, enrolled from relatives or accompanying person were included in the study. Psychological stress was evaluated by the Psychological General Well Being Index short version (PGWBI-S). Sets of the psychological component were generated by principal component analysis (PCA). Association between components was accommodated for confounder and interaction was evaluated by conditional stepwise logistic regression analysis. Psychological component generated was component 1 (depressed mood, lack of positive well being, low vitality, anxiety, low vitality, and low self-control). The odds ratio (OR) of low score of component 1 for OSF was 3.66. Depressed mood, lack of positive well being, low vitality, anxiety, low vitality, and low self-control were associated with OSF. Psychological intervention should, therefore, be included in the management of OSF.
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http://dx.doi.org/10.1080/13548506.2020.1826545DOI Listing
September 2020

Outcomes of luxation injuries to primary teeth-a systematic review.

J Oral Biol Craniofac Res 2020 Apr-Jun;10(2):227-232. Epub 2019 Dec 17.

Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, JamiaMilliaIslamia, New Delhi, India.

Objective: Luxation injuries are one of the most prevalent type traumatic dental injuries in primary dentition. The impact of these injuries may not only be limited to the primary teeth but may also have adverse effects on the developing succedaneous tooth bud resulting in various unfavorable consequences. This systematic review aims at compiling the evidence of available literature regarding luxation injuries to primary teeth, etiology, treatment modalities, outcomes and sequelae on permanent teeth.

Methodology: Search of PubMed, Google Scholar, Cochrane Database of Systematic Reviews, SCOPUS and LILACS virtual health library was conducted for the literature published from January 1, 2007 to December 31, 2017. Two authors separately reviewed the literature and extracted the data from the included studies.

Results: After screening 224 articles, 13 articles fulfilled the inclusion criteria. Most common etiological factor for injury (up to 44.8%) is fall while walking or running. The unfavorable outcomes which are mostly associated with luxation injuries are pulp canal obliteration ranging from 8.6% to 43.3% and pulp necrosis 8.6% -78.9%. Sequelae on succedaneous teeth vary with a high incidence of white or yellow brown discoloration of enamel (78%) and enamel hypoplasia (7.8%-28.3%).

Conclusion: Fall is the most common cause and regular monitoring is recommended for most of the luxated teeth. Pulp canal obliteration, pulp necrosis and tooth loss due to trauma are prevalent complications observed following luxation. White or yellow brown discoloration of enamel and enamel hypoplasia are the most common undesirable sequelae to permanent teeth.
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http://dx.doi.org/10.1016/j.jobcr.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254462PMC
December 2019

The Use of High-Throughput Transcriptomics to Identify Pathways with Therapeutic Significance in Podocytes.

Int J Mol Sci 2019 Dec 31;21(1). Epub 2019 Dec 31.

Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, SC 29425, USA.

Podocytes have a unique structure that supports glomerular filtration function, and many glomerular diseases result in loss of this structure, leading to podocyte dysfunction and ESRD (end stage renal disease). These structural and functional changes involve a complex set of molecular and cellular mechanisms that remain poorly understood. To understand the molecular signature of podocyte injury, we performed transcriptome analysis of cultured human podocytes injured either with PAN (puromycin aminonucleoside) or doxorubicin/adriamycin (ADR). The pathway analysis through DE (differential expression) and gene-enrichment analysis of the injured podocytes showed Tumor protein p53 (P53) as one of the major signaling pathways that was significantly upregulated upon podocyte injury. Accordingly, P53 expression was also up-regulated in the glomeruli of nephrotoxic serum (NTS) and ADR-injured mice. To further confirm these observations, cultured podocytes were treated with the P53 inhibitor pifithrin-α, which showed significant protection from ADR-induced actin cytoskeleton damage. In conclusion, signaling pathways that are involved in podocyte pathogenesis and can be therapeutically targeted were identified by high-throughput transcriptomic analysis of injured podocytes.
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http://dx.doi.org/10.3390/ijms21010274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981397PMC
December 2019

Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers.

Oncotarget 2019 Sep 9;10(52):5389-5402. Epub 2019 Oct 9.

Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA.

Cancers often overexpress anti-apoptotic Bcl-2 proteins for cell death evasion, a recognized hallmark of cancer progression. While estrogen receptor (ER)-α+ breast cancers express high levels of three anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1), pharmacological inhibition of Bcl-2 and/or Bcl-xL fails to induce cell death in ERα+ breast cancer cell lines, due to rapid and robust Mcl-1 upregulation. The mechanisms of acute Mcl-1 upregulation in response to Bcl-2/Bcl-xL inhibition remain undefined in in ERα+ breast cancers. We report here that blockade of Bcl-2 or Bcl-xL, alone or together, rapidly induced mTOR signaling in ERα+ breast cancer cells, rapidly increasing cap-dependent Mcl-1 translation. Cells treated with a pharmacological inhibitor of cap-dependent translation, or with the mTORC1 inhibitor RAD001/everolimus, displayed reduced protein levels of Mcl-1 under basal conditions, and failed to upregulate Mcl-1 protein expression following treatment with ABT-263, a pharmacological inhibitor of Bcl-2 and Bcl-xL. Although treatment with ABT-263 alone did not sustain apoptosis in tumor cells in culture or , ABT-263 plus RAD001 increased apoptosis to a greater extent than either agent used alone. Similarly, combined use of the selective Mcl-1 inhibitor VU661013 with ABT-263 resulted in tumor cell apoptosis and diminished tumor growth . These findings suggest that rapid Mcl-1 translation drives ABT-263 resistance, but can be combated directly using emerging Mcl-1 inhibitors, or indirectly through existing and approved mTOR inhibitors.
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http://dx.doi.org/10.18632/oncotarget.27070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739218PMC
September 2019

Mitochondrial biogenesis induced by the β2-adrenergic receptor agonist formoterol accelerates podocyte recovery from glomerular injury.

Kidney Int 2019 09 6;96(3):656-673. Epub 2019 May 6.

Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, South Carolina, USA. Electronic address:

Podocytes have limited ability to recover from injury. Here, we demonstrate that increased mitochondrial biogenesis, to meet the metabolic and energy demand of a cell, accelerates podocyte recovery from injury. Analysis of events induced during podocyte injury and recovery showed marked upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a transcriptional co-activator of mitochondrial biogenesis, and key components of the mitochondrial electron transport chain. To evaluate our hypothesis that increasing mitochondrial biogenesis enhanced podocyte recovery from injury, we treated injured podocytes with formoterol, a potent, specific, and long-acting β2-adrenergic receptor agonist that induces mitochondrial biogenesis in vitro and in vivo. Formoterol increased mitochondrial biogenesis and restored mitochondrial morphology and the injury-induced changes to the organization of the actin cytoskeleton in podocytes. Importantly, β2-adrenergic receptors were found to be present on podocyte membranes. Their knockdown attenuated formoterol-induced mitochondrial biogenesis. To determine the potential clinical relevance of these findings, mouse models of acute nephrotoxic serum nephritis and chronic (Adriamycin [doxorubicin]) glomerulopathy were used. Mice were treated with formoterol post-injury when glomerular dysfunction was established. Strikingly, formoterol accelerated the recovery of glomerular function by reducing proteinuria and ameliorating kidney pathology. Furthermore, formoterol treatment reduced cellular apoptosis and increased the expression of the mitochondrial biogenesis marker PGC-1α and multiple electron transport chain proteins. Thus, our results support β2-adrenergic receptors as novel therapeutic targets and formoterol as a therapeutic compound for treating podocytopathies.
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http://dx.doi.org/10.1016/j.kint.2019.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708766PMC
September 2019

The motor protein Myo1c regulates transforming growth factor-β-signaling and fibrosis in podocytes.

Kidney Int 2019 07 4;96(1):139-158. Epub 2019 Mar 4.

Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, South Carolina, USA. Electronic address:

Transforming growth factor-β (TGF-β) is known to play a critical role in the pathogenesis of many progressive podocyte diseases. However, the molecular mechanisms regulating TGF-β signaling in podocytes remain unclear. Using a podocyte-specific myosin (Myo)1c knockout, we demonstrate whether Myo1c is critical for TGF-β-signaling in podocyte disease pathogenesis. Specifically, podocyte-specific Myo1c knockout mice were resistant to fibrotic injury induced by Adriamycin or nephrotoxic serum. Further, loss of Myo1c also protected from injury in the TGF-β-dependent unilateral ureteral obstruction mouse model of renal interstitial fibrosis. Mechanistic analyses showed that loss of Myo1c significantly blunted TGF-β signaling through downregulation of canonical and non-canonical TGF-β pathways. Interestingly, nuclear rather than the cytoplasmic Myo1c was found to play a central role in controlling TGF-β signaling through transcriptional regulation. Differential expression analysis of nuclear Myo1c-associated gene promoters showed that nuclear Myo1c targeted the TGF-β responsive gene growth differentiation factor (GDF)-15 and directly bound to the GDF-15 promoter. Importantly, GDF15 was found to be involved in podocyte pathogenesis, where GDF15 was upregulated in glomeruli of patients with focal segmental glomerulosclerosis. Thus, Myo1c-mediated regulation of TGF-β-responsive genes is central to the pathogenesis of podocyte injury. Hence, inhibiting this process may have clinical application in treating podocytopathies.
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http://dx.doi.org/10.1016/j.kint.2019.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589397PMC
July 2019

Disruption of the exocyst induces podocyte loss and dysfunction.

J Biol Chem 2019 06 9;294(26):10104-10119. Epub 2019 May 9.

From the Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425.

Although the slit diaphragm proteins in podocytes are uniquely organized to maintain glomerular filtration assembly and function, little is known about the underlying mechanisms that participate in trafficking these proteins to the correct location for development and homeostasis. Identifying these mechanisms will likely provide novel targets for therapeutic intervention to preserve podocyte function following glomerular injury. Analysis of structural variation in cases of human nephrotic syndrome identified rare heterozygous deletions of in two patients. This suggested that disruption of the highly-conserved eight-protein exocyst trafficking complex could have a role in podocyte dysfunction. Indeed, mRNA profiling of injured podocytes identified significant exocyst down-regulation. To test the hypothesis that the exocyst is centrally involved in podocyte development/function, we generated homozygous podocyte-specific Exoc5 (a central exocyst component that interacts with Exoc4) knockout mice that showed massive proteinuria and died within 4 weeks of birth. Histological and ultrastructural analysis of these mice showed severe glomerular defects with increased fibrosis, proteinaceous casts, effaced podocytes, and loss of the slit diaphragm. Immunofluorescence analysis revealed that Neph1 and Nephrin, major slit diaphragm constituents, were mislocalized and/or lost. mRNA profiling of Exoc5 knockdown podocytes showed that vesicular trafficking was the most affected cellular event. Mapping of signaling pathways and Western blot analysis revealed significant up-regulation of the mitogen-activated protein kinase and transforming growth factor-β pathways in Exoc5 knockdown podocytes and in the glomeruli of podocyte-specific Exoc5 KO mice. Based on these data, we propose that exocyst-based mechanisms regulate Neph1 and Nephrin signaling and trafficking, and thus podocyte development and function.
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http://dx.doi.org/10.1074/jbc.RA119.008362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664173PMC
June 2019

Treatment-Induced Tumor Cell Apoptosis and Secondary Necrosis Drive Tumor Progression in the Residual Tumor Microenvironment through MerTK and IDO1.

Cancer Res 2019 01 9;79(1):171-182. Epub 2018 Nov 9.

Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.

Efferocytosis is the process by which apoptotic cells are cleared from tissue by phagocytic cells. The removal of apoptotic cells prevents them from undergoing secondary necrosis and releasing their inflammation-inducing intracellular contents. Efferocytosis also limits tissue damage by increasing immunosuppressive cytokines and leukocytes and maintains tissue homeostasis by promoting tolerance to antigens derived from apoptotic cells. Thus, tumor cell efferocytosis following cytotoxic cancer treatment could impart tolerance to tumor cells evading treatment-induced apoptosis with deleterious consequences in tumor residual disease. We report here that efferocytosis cleared apoptotic tumor cells in residual disease of lapatinib-treated HER2 mammary tumors in MMTV-Neu mice, increased immunosuppressive cytokines, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg). Blockade of efferocytosis induced secondary necrosis of apoptotic cells, but failed to prevent increased tumor MDSCs, Treg, and immunosuppressive cytokines. We found that efferocytosis stimulated expression of IFN-γ, which stimulated the expression of indoleamine-2,3-dioxegenase (IDO) 1, an immune regulator known for driving maternal-fetal antigen tolerance. Combined inhibition of efferocytosis and IDO1 in tumor residual disease decreased apoptotic cell- and necrotic cell-induced immunosuppressive phenotypes, blocked tumor metastasis, and caused tumor regression in 60% of MMTV-Neu mice. This suggests that apoptotic and necrotic tumor cells, via efferocytosis and IDO1, respectively, promote tumor 'homeostasis' and progression. SIGNIFICANCE: These findings show in a model of HER2 breast cancer that necrosis secondary to impaired efferocytosis activates IDO1 to drive immunosuppression and tumor progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1106DOI Listing
January 2019

Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers.

Cancer Res 2018 11 17;78(21):6183-6195. Epub 2018 Sep 17.

Cancer Biology Graduate Program, Vanderbilt University School of Medicine, Nashville, Tennessee.

Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum but have not achieved widespread success in breast cancers, a tumor type considered poorly immunogenic and which harbors a decreased presence of tumor-infiltrating lymphocytes. Approaches that activate innate immunity in breast cancer cells and the tumor microenvironment are of increasing interest, based on their ability to induce immunogenic tumor cell death, type I IFNs, and lymphocyte-recruiting chemokines. In agreement with reports in other cancers, we observe loss, downregulation, or mutation of the innate viral nucleotide sensor retinoic acid-inducible gene I (RIG-I/) in only 1% of clinical breast cancers, suggesting potentially widespread applicability for therapeutic RIG-I agonists that activate innate immunity. This was tested using an engineered RIG-I agonist in a breast cancer cell panel representing each of three major clinical breast cancer subtypes. Treatment with RIG-I agonist resulted in upregulation and mitochondrial localization of RIG-I and activation of proinflammatory transcription factors STAT1 and NF-κB. RIG-I agonist triggered the extrinsic apoptosis pathway and pyroptosis, a highly immunogenic form of cell death in breast cancer cells. RIG-I agonist also induced expression of lymphocyte-recruiting chemokines and type I IFN, confirming that cell death and cytokine modulation occur in a tumor cell-intrinsic manner. Importantly, RIG-I activation in breast tumors increased tumor lymphocytes and decreased tumor growth and metastasis. Overall, these findings demonstrate successful therapeutic delivery of a synthetic RIG-I agonist to induce tumor cell killing and to modulate the tumor microenvironment These findings describe the first in vivo delivery of RIG-I mimetics to tumors, demonstrating a potent immunogenic and therapeutic effect in the context of otherwise poorly immunogenic breast cancers. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0730DOI Listing
November 2018

Blocking "don't eat me" signal of CD47-SIRPα in hematological malignancies, an in-depth review.

Blood Rev 2018 11 14;32(6):480-489. Epub 2018 Apr 14.

Department of Medicine, Division of Hematology, Oncology, Arizona Cancer Center, The University of Arizona, Tucson, AZ, USA. Electronic address:

Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.
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http://dx.doi.org/10.1016/j.blre.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186508PMC
November 2018

Safety and feasibility evaluation of tourniquets for total knee replacement (SAFE-TKR): study protocol.

BMJ Open 2018 04 10;8(4):e022067. Epub 2018 Apr 10.

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

Introduction: This study is designed to determine whether a full randomised controlled trial (RCT) examining the clinical effectiveness and safety of total knee replacement surgery with or without a tourniquet is warranted and feasible.

Method And Analysis: Single centre, patient-blinded and assessor-blinded RCT. A computer-generated randomisation service will allocate 50 participants into one of two trial treatments, surgery with or without a tourniquet. The primary objective is to estimate recruitment, crossovers and follow-up of patients. All patients will have an MRI scan of their brain preoperatively and day 1 or 2 postoperatively to identify ischaemic cerebral emboli (primary clinical outcome). Oxford Cognitive Screen, Montreal Cognitive Assessment and Mini-Mental State Examination will be evaluated as outcome tools for measuring cognitive impairment at days 1, 2 and 7 postoperatively. Thigh pain, blood transfusion requirements, venous thromboembolism, revision surgery, surgical complications, mortality and Oxford knee and five-level EuroQol-5D scores will be collected over 12 months. : 30 trial patients and 20 knee surgeons will take part in semistructured interviews. Interviews will capture views regarding the pilot trial and explore barriers and potential solutions to a full trial. : UK National Joint Registry data will be linked to Hospital Episode Statistics to estimate the relationship between tourniquet use and venous thromboembolic event, length of hospital stay, risk of revision surgery and death. The study will conclude with a multidisciplinary workshop to reach a consensus on whether a full trial is warranted and feasible.

Ethics And Dissemination: National Research Ethics Committee (West Midlands-Edgbaston) approved this study on 27 January 2016 (15/WM/0455). The study is sponsored by University of Warwick and University Hospitals Coventry and Warwickshire. The results will be disseminated via high-impact peer-reviewed publication.

Trial Registration Number: ISRCTN20873088; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900804PMC
April 2018

Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers.

Cell Death Dis 2018 01 17;9(2):21. Epub 2018 Jan 17.

Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Estrogen receptor-α positive (ERα+) breast cancer accounts for approximately 70-80% of the nearly 25,0000 new cases of breast cancer diagnosed in the US each year. Endocrine-targeted therapies (those that block ERα activity) serve as the first line of treatment in most cases. Despite the proven benefit of endocrine therapies, however, ERα+ breast tumors can develop resistance to endocrine therapy, causing disease progression or relapse, particularly in the metastatic setting. Anti-apoptotic Bcl-2 family proteins enhance breast tumor cell survival, often promoting resistance to targeted therapies, including endocrine therapies. Herein, we investigated whether blockade of anti-apoptotic Bcl-2 family proteins could sensitize luminal breast cancers to anti-estrogen treatment. We used long-term estrogen deprivation (LTED) of human ERα+ breast cancer cell lines, an established model of sustained treatment with and acquired resistance to aromatase inhibitors (AIs), in combination with Bcl-2/Bcl-xL inhibition (ABT-263), finding that ABT-263 induced only limited tumor cell killing in LTED-selected cells in culture and in vivo. Interestingly, expression and activity of the Bcl-2-related factor Mcl-1 was increased in LTED cells. Genetic Mcl-1 ablation induced apoptosis in LTED-selected cells, and potently increased their sensitivity to ABT-263. Increased expression and activity of Mcl-1 was similarly seen in clinical breast tumor specimens treated with AI + the selective estrogen receptor downregulator fulvestrant. Delivery of Mcl-1 siRNA loaded into polymeric nanoparticles (MCL1 si-NPs) decreased Mcl-1 expression in LTED-selected and fulvestrant-treated cells, increasing tumor cell death and blocking tumor cell growth. These findings suggest that Mcl-1 upregulation in response to anti-estrogen treatment enhances tumor cell survival, decreasing response to therapeutic treatments. Therefore, strategies blocking Mcl-1 expression or activity used in combination with endocrine therapies would enhance tumor cell death.
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http://dx.doi.org/10.1038/s41419-017-0072-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833697PMC
January 2018

The Retinol Binding Protein Receptor 2 (Rbpr2) is required for Photoreceptor Outer Segment Morphogenesis and Visual Function in Zebrafish.

Sci Rep 2017 11 24;7(1):16207. Epub 2017 Nov 24.

Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA.

Vitamin A (all-trans retinol) plays critical roles in mammalian development and vision. Since vitamin A is food-derived, tissue-specific uptake and storage mechanism are needed. In the eye, uptake of RBP4-retinol is mediated by the receptor Stra6, whereas the receptor mediating RBP4 binding and retinol transport into the liver has just recently been discovered. Here we examined the role of zebrafish retinol binding protein receptor 2 (Rbpr2) for RBP4-retinol uptake in developing embryos, using eye development and vision as sensitive readouts. In cultured cells, Rbpr2 localized to membranes and promoted RBP4-retinol uptake. In larvae, Rbpr2 expression was detected in developing intestinal enterocytes and liver hepatocytes. Two rbpr2 mutant zebrafish lines, each resulting in Rbpr2 deficiency, exhibit a small eye defect, and systemic malformations including hydrocephaly and cardiac edema, phenotypes associated with vitamin A deficiency. In the retina, Rbpr2 loss resulted in shorter photoreceptor outer segments, mislocalization and decrease in visual pigments, decreased expression of retinoic acid-responsive genes and photoreceptor cell loss, overall leading to a reduction of visual function. Together, these results demonstrate that Rbpr2-mediated RBP4-retinol uptake in developing liver and intestine is necessary to provide sufficient substrate for ocular retinoid production required for photoreceptor cell maintenance and visual function.
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http://dx.doi.org/10.1038/s41598-017-16498-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701214PMC
November 2017

Anti-CD 19 and anti-CD 20 CAR-modified T cells for B-cell malignancies: a systematic review and meta-analysis.

Immunotherapy 2017 09;9(12):979-993

University of Arizona, Department of Medicine, Hematology & Oncology, Tucson, AZ, 85724 USA.

Chimeric antigen receptor modified T cells targeting CD19 and CD20 have shown activity in Phase I, II trials of patients with hematological malignancies. We conducted a systematic review and meta-analysis of all published clinical trials studying the role of efficacy as well as safety of CD-19 and CD-20 chimeric antigen receptor-T therapy for B-cell hematologic malignancies. A total of 16 studies with 195 patients were identified. The pooled analysis showed an overall response rate of 61% (118/195) with complete response of 42% (81/195) and partial response of 19% (37/195). Major adverse events were cytokine release syndrome 33%, neurotoxicity 33% and B-cell aplasia 54%. Collectively, the results indicate encouraging response in relapsed/refractory B lymphoma and leukemia, especially in acute lymphoblastic leukemia (ALL) patients.
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http://dx.doi.org/10.2217/imt-2017-0062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040074PMC
September 2017

ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation.

Breast Cancer Res 2017 Sep 8;19(1):105. Epub 2017 Sep 8.

Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Rm 749 Preston Research Building, Nashville, TN, 37232, USA.

Background: During pregnancy, as the mammary gland prepares for synthesis and delivery of milk to newborns, a luminal mammary epithelial cell (MEC) subpopulation proliferates rapidly in response to systemic hormonal cues that activate STAT5A. While the receptor tyrosine kinase ErbB4 is required for STAT5A activation in MECs during pregnancy, it is unclear how ErbB3, a heterodimeric partner of ErbB4 and activator of phosphatidyl inositol-3 kinase (PI3K) signaling, contributes to lactogenic expansion of the mammary gland.

Methods: We assessed mRNA expression levels by expression microarray of mouse mammary glands harvested throughout pregnancy and lactation. To study the role of ErbB3 in mammary gland lactogenesis, we used transgenic mice expressing WAP-driven Cre recombinase to generate a mouse model in which conditional ErbB3 ablation occurred specifically in alveolar mammary epithelial cells (aMECs).

Results: Profiling of RNA from mouse MECs isolated throughout pregnancy revealed robust Erbb3 induction during mid-to-late pregnancy, a time point when aMECs proliferate rapidly and undergo differentiation to support milk production. Litters nursed by ErbB3 dams weighed significantly less when compared to litters nursed by ErbB3 dams. Further analysis revealed substantially reduced epithelial content, decreased aMEC proliferation, and increased aMEC cell death during late pregnancy. Consistent with the potent ability of ErbB3 to activate cell survival through the PI3K/Akt pathway, we found impaired Akt phosphorylation in ErbB3 samples, as well as impaired expression of STAT5A, a master regulator of lactogenesis. Constitutively active Akt rescued cell survival in ErbB3-depleted aMECs, but failed to restore STAT5A expression or activity. Interestingly, defects in growth and survival of ErbB3 aMECs as well as Akt phosphorylation, STAT5A activity, and expression of milk-encoding genes observed in ErbB3 MECs progressively improved between late pregnancy and lactation day 5. We found a compensatory upregulation of ErbB4 activity in ErbB3 mammary glands. Enforced ErbB4 expression alleviated the consequences of ErbB3 ablation in aMECs, while combined ablation of both ErbB3 and ErbB4 exaggerated the phenotype.

Conclusions: These studies demonstrate that ErbB3, like ErbB4, enhances lactogenic expansion and differentiation of the mammary gland during pregnancy, through activation of Akt and STAT5A, two targets crucial for lactation.
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http://dx.doi.org/10.1186/s13058-017-0893-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591538PMC
September 2017

All That Wheezes Is Not Asthma: A Case of Diffuse Large B-Cell Lymphoma of the Larynx.

Case Rep Oncol Med 2017 15;2017:7072615. Epub 2017 Mar 15.

Department of Medicine, University of Arizona, Tucson, AZ, USA.

Localized laryngeal lymphoma is a rare entity with an incidence of less than 1% of all laryngeal neoplasms. Diffuse large B-cell lymphoma (DLBCL) is the most common type of laryngeal neoplasms. Here, we describe a case of a young 28-year-old female with large B-cell lymphoma who remained undiagnosed for a long time owing to a myriad of nonspecific presentation including "wheezing." Although primary laryngeal lymphomas constitute a diagnostic challenge since they are rare, one should have a high index of suspicion for lymphoma of the larynx in patients presenting with unresolved wheezing as it can present catastrophically with acute airway obstruction requiring immediate surgical intervention which was observed in this case. Treatment includes radiotherapy, chemotherapy, immunotherapy, or a combination of these. We hope that the discussions ensuing from case reports regarding uncommon presentations of laryngeal lymphoma may spur the formation of regional/international databases for the description of lymphomas with unusual presentations. This effort can lead to in-depth study of cases and prompt awareness of "rare and subtle presentations" of laryngeal lymphoma.
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http://dx.doi.org/10.1155/2017/7072615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371224PMC
March 2017

Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia.

Genes Chromosomes Cancer 2017 07 4;56(7):535-547. Epub 2017 Apr 4.

Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37232.

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. The Tff1 knockout (KO) mouse model develops gastric lesions that include low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinomas. In this study, we used Affymetrix microarrays gene expression platforms for analysis of molecular signatures in the mouse stomach [Tff1-KO (LGD) and Tff1 wild-type (normal)] and human gastric cancer tissues and their adjacent normal tissue samples. Combined integrated bioinformatics analysis of mouse and human datasets indicated that 172 genes were consistently deregulated in both human gastric cancer samples and Tff1-KO LGD lesions (P < .05). Using Ingenuity pathway analysis, these genes mapped to important transcription networks that include MYC, STAT3, β-catenin, RELA, NFATC2, HIF1A, and ETS1 in both human and mouse. Further analysis demonstrated activation of FOXM1 and inhibition of TP53 transcription networks in human gastric cancers but not in Tff1-KO LGD lesions. Using real-time RT-PCR, we validated the deregulated expression of several genes (VCAM1, BGN, CLDN2, COL1A1, COL1A2, COL3A1, EpCAM, IFITM1, MMP9, MMP12, MMP14, PDGFRB, PLAU, and TIMP1) that map to altered transcription networks in both mouse and human gastric neoplasia. Our study demonstrates significant similarities in deregulated transcription networks in human gastric cancer and gastric tumorigenesis in the Tff1-KO mouse model. The data also suggest that activation of MYC, STAT3, RELA, and β-catenin transcription networks could be an early molecular step in gastric carcinogenesis.
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http://dx.doi.org/10.1002/gcc.22456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524517PMC
July 2017

Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade.

Mol Cancer Res 2017 03 30;15(3):259-268. Epub 2016 Dec 30.

Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.

An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of as compared with or (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured using Mcl-1/Bim proximity ligation assays. Importantly, gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of or and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1-selective inhibitors for targeted tumor cell killing. Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. .
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http://dx.doi.org/10.1158/1541-7786.MCR-16-0280-TDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334148PMC
March 2017

Corporate governance and the adoption of health information technology within integrated delivery systems.

Health Care Manage Rev 2014 Jul-Sep;39(3):234-44

Aaron Baird, PhD, MBA, is Assistant Professor, Institute of Health Administration and Center for Health Information Technology, J. Mack Robinson College of Business, Georgia State University, P.O. Box 3988, Atlanta. E-mail: Michael F. Furukawa, PhD, is Director, Office of Economic Analysis, Evaluation, and Modeling, Office of the National Coordinator for Health Information Technology, Department of Health and Human Services, Washington, DC. E-mail: Bushra Rahman, MBA, MHSM, is Research Administrator, Health Sector Supply Chain Research Consortium, Department of Supply Chain Management, W.P. Carey School of Business, Arizona State University, P.O. Box 874706, Tempe. Eugene S. Schneller, PhD, is Dean's Council of 100 Distinguished Scholar, Department of Supply Chain Management, W.P. Carey School of Business, Arizona State University, P.O. Box 874706, Tempe.

Background: Although several previous studies have found "system affiliation" to be a significant and positive predictor of health information technology (IT) adoption, little is known about the association between corporate governance practices and adoption of IT within U.S. integrated delivery systems (IDSs).

Purposes: Rooted in agency theory and corporate governance research, this study examines the association between corporate governance practices (centralization of IT decision rights and strategic alignment between business and IT strategy) and IT adoption, standardization, and innovation within IDSs.

Methodology/approach: Cross-sectional, retrospective analyses using data from the 2011 Health Information and Management Systems Society Analytics Database on adoption within IDSs (N = 485) is used to analyze the correlation between two corporate governance constructs (centralization of IT decision rights and strategic alignment) and three IT constructs (adoption, standardization, and innovation) for clinical and supply chain IT. Multivariate fractional logit, probit, and negative binomial regressions are applied.

Findings: Multivariate regressions controlling for IDS and market characteristics find that measures of IT adoption, IT standardization, and innovative IT adoption are significantly associated with centralization of IT decision rights and strategic alignment. Specifically, centralization of IT decision rights is associated with 22% higher adoption of Bar Coding for Materials Management and 30%-35% fewer IT vendors for Clinical Data Repositories and Materials Management Information Systems. A combination of centralization and clinical IT strategic alignment is associated with 50% higher Computerized Physician Order Entry adoption, and centralization along with supply chain IT strategic alignment is significantly negatively correlated with Radio Frequency Identification adoption

Practice Implications: : Although IT adoption and standardization are likely to benefit from corporate governance practices within IDSs, innovation is likely to be delayed. In addition, corporate governance is not one-size-fits-all, and contingencies are important considerations.
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http://dx.doi.org/10.1097/HMR.0b013e318294e5e6DOI Listing
February 2015

High blood manganese in iron-deficient children in Karachi.

Public Health Nutr 2013 Sep 27;16(9):1677-83. Epub 2013 Mar 27.

Karachi Institute of Biotechnology and Genetic Engineering, University of Karachi, Karachi, Pakistan.

Objective: Dietary Fe deficiency has a high incidence in Pakistani children and may be associated with increased gastrointestinal absorption of trace metals such as Mn. Therefore, children residing in heavily polluted cities like Karachi may be prone to Mn toxicity. The present study investigated blood Mn concentrations in Karachi children of different Fe statuses.

Design: A prospective observational study was conducted where children were classified into different categories of Fe status – normal Fe, borderline Fe deficiency, Fe deficiency and Fe-deficiency anaemia – using WHO criteria supported by measurements of soluble transferrin receptors. Blood Mn was determined for children in each category using graphite atomic absorption spectroscopy.

Setting: Three hospital outpatient departments in Karachi, Pakistan.

Subjects: A total of 269 children (156 males, 113 females) aged 6–60 months from low-income families of Karachi.

Results: Blood Mn concentrations were significantly higher in children with Fe-deficiency anaemia and Fe deficiency compared with those of normal Fe status (both P,0?01). Blood concentrations of soluble transferrin receptors were higher in children with Fe-deficiency anaemia compared with those of borderline or normal Fe status (both P,0?05).

Conclusions: These findings report for the first time high blood Mn concentrations in Fe-deficient children of this age group. There is therefore an urgent need to identify and remove environmental exposure to Mn in combination with health strategies aimed at eradicating childhood Fe deficiency.
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http://dx.doi.org/10.1017/S1368980013000839DOI Listing
September 2013

Blood and hair lead in children with different extents of iron deficiency in Karachi.

Environ Res 2012 Oct 21;118:94-100. Epub 2012 Aug 21.

Karachi Institute of Biotechnology and Genetic Engineering, University of Karachi, Karachi-75270, Pakistan.

Childhood iron deficiency has a high incidence in Pakistan. Some but not all studies have shown that dietary iron deficiency may cause increased absorption of lead as both compete for the same transporters in the small intestine. Therefore, children in Pakistan, residing in heavily polluted cities like Karachi may be prone to lead poisoning. This hypothesis was tested by investigating blood and hair lead concentrations in children from Karachi who were divided into four groups of iron status; normal, borderline iron deficiency, iron deficiency and iron deficiency anaemia. A prospective observational study was conducted where 269 children were categorized into four groups of iron status using the World Health Organization criteria and one based on soluble transferrin receptor measurements. Blood iron status was determined using a full blood count, serum iron, ferritin, transferrin saturation and soluble transferrin receptor measurements. Blood lead was determined by graphite atomic absorption spectroscopy, whereas hair lead was assessed using an inductively coupled plasma atomic emission spectroscopy technique. Blood lead concentrations were significantly higher in children with iron deficiency anaemia (mean [95% confidence intervals] were 24.9 [22.6-27.2] μg/dL) compared to those with normal iron status (19.1 [16.8-21.4] μg/dL) using WHO criteria. In contrast, hair lead content was not significantly different in children of different iron status. Our findings reinforce the importance of not only reducing environmental lead pollution but also the development of national health strategies to reduce childhood iron deficiency in Pakistan.
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http://dx.doi.org/10.1016/j.envres.2012.07.004DOI Listing
October 2012

Malignant tumors of the minor salivary glands in northern Pakistan: a clinicopathological study.

Hematol Oncol Stem Cell Ther 2008 Apr-Jun;1(2):90-3

Department of Histopathology, Armed Forces Institute of Pathology Rawalpindi, Punjab, Pakistan.

Background: Malignant tumors of the minor salivary glands comprise a small but significant proportion of oral cancers. We analyzed this group of tumors in our population.

Methods: The records of all cases of malignant minor salivary gland tumors diagnosed at the Armed Forces Institute of Pathology (AFIP), Rawalpindi, Pakistan, during a period of 10 years (1994-2003) are described. The institute receives biopsy material from armed forces and public and private sector hospitals in northern Pakistan as well as referrals for second opinion.

Results: A total of 21168 tumors were recorded at the AFIP Tumor Registry during the study period. These included 70 malignant minor salivary gland tumors. Twenty-three of these (32.8%) arose in the palate while the remaining tumors originated at other sites in the oral cavity. The commonest histological type was adenoid cystic carcinoma, constituting 30 cases (42.8%). The next most common type was mucoepidermoid carcinoma comprising 26 (37.1%) cases. The mean age of cases was 43.4 years and the male-to-female ratio was 1:1.4. There were 2 cases each of polymorphous low-grade adenocarcinoma and clear cell adenocarcinoma. The remaining cases included undifferentiated carcinomas, adenocarcinomas (not otherwise specified) and a few other rare tumors.

Conclusion: Adenoid cystic carcinoma was the commonest malignant neoplasm of the minor salivary glands followed by mucoepidermoid carcinoma. The palate was the commonest location of these tumors.
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http://dx.doi.org/10.1016/s1658-3876(08)50039-2DOI Listing
February 2010
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