Publications by authors named "Nasrin Khan"

14 Publications

  • Page 1 of 1

Sodium bisulfite pyrosequencing revealed that developmental exposure to environmental contaminant mixtures does not affect DNA methylation of DNA repeats in Sprague-Dawley rats.

J Toxicol Environ Health A 2017 1;80(1):32-52. Epub 2016 Dec 1.

a Health Canada, Healthy Environments and Consumer Safety Branch, Environmental Health Sciences and Research Bureau , Ottawa , Ontario , Canada.

Hypomethylation of DNA repeats has been linked to diseases and cancer predisposition. Human studies suggest that higher blood concentrations of environmental contaminants (EC) correlate with levels of hypomethylation of DNA repeats in blood. The objective of this study was to examine the effect of in utero and/or lactational exposure to EC on the methylation of DNA repeats (LINE-1 and identifier element) in Sprague-Dawley rat pups at birth, at postnatal day (PND) 21, and in adulthood (PND78-86). From gestation day 0 to PND20, dams were exposed to a mixture "M" of polychlorinated biphenyls (PCB), pesticides, and methylmercury (MeHg), at 0.5 or 1 mg/kg/d (0.5M and M). At birth, some control (C) and M litters were cross-fostered to create the following in utero/postnatal exposure groups: C/C, M/C, C/M, M/M. Additional dams received 1.8 ng/kg/d of a mixture of aryl-hydrocarbon receptor (AhR) agonists (non-ortho-PCB, PC-dibenzodioxins, and PC-dibenzofurans) without or with 0.5M (0.5MAhR). Measurements of EC residue levels confirmed differences in their accumulation across treatments, age, and tissues. Although induction of hepatic detoxification enzyme activities (cytochrome P-450) demonstrated biological effects of treatments, the assessment of methylation in DNA repeats by sodium bisulfite pyrosequencing of liver, spleen, and thymus samples revealed no marked treatment-related effects but significant tissue- and age-related methylation differences. Further studies are required to determine whether absence of significant observable treatment effects on methylation of DNA repeats in the rat relate to tissue, strain, or species differences.
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http://dx.doi.org/10.1080/15287394.2016.1231644DOI Listing
May 2017

Direct detection of endogenous MicroRNAs and their post-transcriptional modifications in cancer serum by capillary electrophoresis-mass spectrometry.

Anal Bioanal Chem 2016 Apr 14;408(11):2891-9. Epub 2016 Jan 14.

Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, K1N 6 N5, Canada.

MicroRNA molecules (miRNAs) are a class of small, single-stranded, non-coding RNA molecules that regulate cellular messenger RNA and their corresponding proteins. Extracellular miRNAs circulate in the bloodstream inside exosomes or in complexes with proteins and lipoproteins. The miRNA sequences and their quantitative levels are used as unique signatures associated with cancer diagnosis and prognosis after anticancer treatment. MicroRNAs are modified through a series of processing events after transcription like 5'-end phosphorylation, 3'- end adenylation or uridylation, terminal nucleotide deletion. The problem is that existing bioanalytical methods such as microarrays and a quantitative polymerase chain reaction are sensitive, but not capable of identifying the post-transcriptional modifications of miRNA. Here we report a capillary electrophoresis-mass spectrometry (CE-MS) method, which performs a multiplex, direct analysis of miRNAs from biological samples. Using the CE-MS method, we detected two endogenous human circulating miRNAs, a 23-nucleotide long 5'-phosporylated miRNA with 3'-uridylation (iso-miR-16-5p), and a 22-nucleotide long 5'-phosporylated miRNA (miR-21-5p) isolated from B-cell chronic lymphocytic leukemia serum. The CE separation and following MS analysis provides label-free quantitation and reveals modifications of miRNAs. MicroRNA profiling of serum samples with CE-MS has the potential to be a versatile and minimally invasive bioassay that could lead to better clinical diagnostics and disease treatment.
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http://dx.doi.org/10.1007/s00216-015-9277-yDOI Listing
April 2016

Protein electrocatalysis for direct sensing of circulating microRNAs.

Anal Chem 2015 Jan 26;87(2):1395-403. Epub 2014 Dec 26.

Department of Chemistry, University of Ottawa , 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada.

MicroRNAs (miRNAs) are potentially useful biomarkers for diagnosis, classification, and prognosis of many diseases, including cancer. Herein, we developed a protein-facilitated electrocatalytic quadroprobe sensor (Sens(PEQ)) for detection of miRNA signature of chronic lymphocytic leukemia (CLL) in human serum. The developed signal-ON sensor provides a compatible combination of two DNA adaptor strands modified with four methylene blue molecules and electrocatalysis using glucose oxidase in order to enhance the overall signal gain. This enhanced sensitivity provided the response necessary to detect the low-abundant serum miRNAs without preamplification. The developed Sens(PEQ) is exquisitely sensitive to subtle π-stack perturbations and capable of distinguishing single base mismatches in the target miRNA. Furthermore, the developed sensor was employed for profiling of three endogenous miRNAs characteristic to CLL, including hsa-miR-16-5p, hsa-miR-21-5p, and hsa-miR-150-5p in normal healthy serum, chronic lymphocytic leukemia Rai stage 1 (CLL-1), and stage 3 (CLL-3) sera, using a non-human cel-miR-39-3p as an internal standard. The sensor results were verified by conventional SYBR green-based quantitative reverse-transcription polymerase chain reaction (RT-qPCR) analysis.
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http://dx.doi.org/10.1021/ac504331cDOI Listing
January 2015

A young pregnant woman with spontaneous carotid artery dissection--unknown mechanisms.

BMJ Case Rep 2014 May 30;2014. Epub 2014 May 30.

Stafford Hospital, Stafford, UK.

Spontaneous carotid artery dissection in pregnancy has not been reported before. We present a case of a 31-year-old Caucasian woman who was 11 weeks pregnant and presented with neck pain, headache, vomiting and left side Horner's syndrome. Subsequent investigations with MR angiography confirmed spontaneous left internal carotid artery dissection.
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http://dx.doi.org/10.1136/bcr-2013-202541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039886PMC
May 2014

Conformational Dynamics of DNA G-Quadruplex in Solution Studied by Kinetic Capillary Electrophoresis Coupled On-line with Mass Spectrometry.

ChemistryOpen 2014 Apr 2;3(2):58-64. Epub 2014 Apr 2.

Department of Chemistry, University of Ottawa 10 Marie Curie, Ottawa K1N 6N5 (Canada).

G-quadruplex-forming DNA/RNA sequences play an important role in the regulation of biological functions and development of new anticancer and anti-aging drugs. In this work, we couple on-line kinetic capillary electrophoresis with mass spectrometry (KCE-MS) to study conformational dynamics of DNA G-quadruplexes in solution. We show that peaks shift and its widening in KCE can be used for measuring rate and equilibrium constants for DNA-metal affinity interactions and G-quadruplex formation; and ion mobility mass spectrometry (IM-MS) provides information about relative sizes, absolute molecular masses and stoichiometry of DNA complexes. KCE-MS separates a thrombin-binding aptamer d[GGTTGGTGTGGTTGG] from mutated sequences based on affinity to potassium, and reveals the apparent equilibrium folding constant (K F≈150 μm), folding rate constant (k on≈1.70×10(3) s(-1) m(-1)), unfolding rate constant (k off≈0.25 s(-1)), half-life time of the G-quadruplex (t 1/2≈2.8 s), and relaxation time (τ≈3.9 ms at physiological 150 mm [K(+)]). In addition, KCE-MS screens for a GQ-stabilizing/-destabilizing effect of DNA binding dyes and an anticancer drug, cisplatin.
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http://dx.doi.org/10.1002/open.201400002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000168PMC
April 2014

Four-way junction formation promoting ultrasensitive electrochemical detection of microRNA.

Anal Chem 2013 Oct 23;85(20):9422-7. Epub 2013 Sep 23.

Department of Chemistry, University of Ottawa , 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada.

MicroRNAs (miRNAs) represent a class of biomarkers that are frequently deregulated in cancer cells and have shown a great promise for cancer classification and prognosis. Here, we endeavored to develop a DNA four-way junction based electrochemical sensor (4J-SENS) for ultrasensitive miRNA analysis. The developed sensor can be operated within the dynamic range from 10 aM to 1 fM and detect as low as 2 aM of miR-122 (∼36 molecules per sample), without PCR amplification. Furthermore, the 4J-SENS was employed to profile endogenouse hsa-miR-122 in healthy human and chronic lymphocyitc leukemia (CLL) patient serum, and the results were validated by qPCR analysis.
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http://dx.doi.org/10.1021/ac402416zDOI Listing
October 2013

Quantitative analysis of microRNA in blood serum with protein-facilitated affinity capillary electrophoresis.

Methods Mol Biol 2013 ;1039:245-59

University of Ottawa, Ottawa, ON, Canada.

MicroRNAs play an important role in gene regulation and disease etiology and are blood-based biomarkers of diseases. Here, we describe a protein-facilitated affinity capillary electrophoresis (ProFACE) method for ultra-sensitive direct miRNA detection as low as 300,000 molecules in 1 mL of blood serum, using single-stranded DNA binding protein (SSB) and double-stranded RNA binding protein (p19) as separation enhancers. This method utilizes either the selective binding of SSB to a fluorescent single-stranded DNA/RNA probe or the binding of p19 to miRNA-RNA probe duplex.
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http://dx.doi.org/10.1007/978-1-62703-535-4_20DOI Listing
March 2014

Three-mode electrochemical sensing of ultralow microRNA levels.

J Am Chem Soc 2013 Feb 11;135(8):3027-38. Epub 2013 Feb 11.

Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada.

MicroRNAs (miRNAs) are an emerging class of biomarkers that are frequently deregulated in cancer cells and have shown great promise for cancer classification and prognosis. In this work, we developed a three-mode electrochemical sensor for detection and quantitation of ultralow levels of miRNAs in a wide dynamic range of measured concentrations. The sensor facilitates three detection modalities based on hybridization (H-SENS), p19 protein binding (P-SENS), and protein displacement (D-SENS). The combined three-mode sensor (HPD-SENS) identifies as low as 5 aM or 90 molecules of miRNA per 30 μL of sample without PCR amplification, and can be operated within the dynamic range from 10 aM to 1 μM. The HPD sensor is made on a commercially available gold nanoparticles-modified electrode and is suitable for analyzing multiple miRNAs on a single electrode. This three-mode sensor exhibits high selectivity and specificity and was used for sequential analysis of miR-32 and miR-122 on one electrode. In addition, the H-SENS can recognize miRNAs with different A/U and G/C content and distinguish between a fully matched miRNA and a miRNA comprising either a terminal or a middle single base mutation. Furthermore, the H- and P-SENS were successfully employed for direct detection and profiling of three endogenous miRNAs, including hsa-miR-21, hsa-miR-32, and hsa-miR-122 in human serum, and the sensor results were validated by qPCR.
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http://dx.doi.org/10.1021/ja308216zDOI Listing
February 2013

Quantitative analysis of microRNA in blood serum with protein-facilitated affinity capillary electrophoresis.

Anal Chem 2011 Aug 18;83(16):6196-201. Epub 2011 Jul 18.

Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada.

MicroRNAs (miRNAs) are small (∼22 nt) regulatory RNAs that are frequently deregulated in cancer and have shown promise as tissue- and blood-based biomarkers for cancer classification and prognostication. Here we present a protein-facilitated affinity capillary electrophoresis (ProFACE) assay for rapid quantification of miRNA levels in blood serum using single-stranded DNA binding protein (SSB) and double-stranded RNA binding protein (p19) as separation enhancers. The method utilizes either the selective binding of SSB to a single-stranded DNA/RNA probe or the binding of p19 to miRNA-RNA probe duplex. For the detection of ultralow amounts of miRNA without polymerase chain reaction (PCR) amplification in blood samples we apply off-line preconcentration of synthetic miRNA-122 from serum by p19-coated magnetic beads followed by online sample stacking in the ProFACE assay. The detection limit is 0.5 fM or 30 000 miRNA molecules in 1 mL of serum as a potential source of naïve miRNAs.
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http://dx.doi.org/10.1021/ac2016213DOI Listing
August 2011

Predictors of short term mortality in heart failure - insights from the Euro Heart Failure survey.

Int J Cardiol 2010 Jan 11;138(1):63-9. Epub 2008 Sep 11.

Department of Academic Cardiology, University of Hull, UK.

Objective: To identify factors associated with short term mortality in hospitalised patients with heart failure.

Background: Hospitalisation is frequent in patients with heart failure and is associated with a high mortality.

Methods: The Euro Heart Failure survey collected data from patients with suspected heart failure. We searched this data for predictors of short term mortality.

Results: Of 10,701 patients, 1404 (13%) died within 12 weeks of admission. On univariate analysis, increasing age, hyponatraemia, renal impairment, hyperkalaemia, anaemia, severe mitral regurgitation, severe LV systolic dysfunction(LVSD), increasing QRS and female sex carried adverse prognosis. ACEI, beta-blockers, nitrates, anti-thrombotic and lipid lowering drugs were associated with a better prognosis. On multivariable analysis the following provided independent prognostic information: increasing age (OR per SD=1.5, 95% CI 1.4-1.6), severe LVSD (1.8, 1.5-2.1), serum creatinine (1.2, 1.2-1.3), sodium (0.9, 0.8-0.9), Hb (0.9, 0.8-0.9) and treatment with ACEI (0.5, 0.5-0.6), beta-blockers (0.7, 0.6-0.8), statins (0.6, 0.5-0.7), calcium channel blockers (0.7, 0.6-0.8), warfarin (0.5, 0.4-0.6), heparin (1.7, 1.4-1.9), anti-platelet drugs (0.6, 0.5-0.6) and need for inotropes (5.5, 4.6-6.6). A simple risk score (range 0-11) identified cohorts with a 12 week mortality ranging from 2% to 44%.

Conclusions: Simple and readily available clinical variables and a risk score based on medical history and routine tests that all patients admitted with heart failure have, can identify patients with good, intermediate and high short term mortality.
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http://dx.doi.org/10.1016/j.ijcard.2008.08.004DOI Listing
January 2010

The timing of development and subsequent clinical course of heart failure after a myocardial infarction.

Eur Heart J 2008 Apr 19;29(7):859-70. Epub 2008 Mar 19.

Department of Cardiology, Hull Royal Infirmary, University of Hull Castle Hill Hospital, Kingston-upon-Hull, Castle Road, Cottingham, East Yorkshire HU16 5JQ, UK.

Aims: Myocardial infarction (MI) is a common cause of heart failure (HF), which may develop early and persist or resolve, or develop late. The cumulative incidence, persistence, and resolution of HF after MI are poorly described. The aim of this study is to describe the natural history and prognosis of HF after an MI.

Methods And Results: Patients with a death or discharge diagnosis of MI in 1998 were identified from records of hospitals providing services to a local community of 600 000 people. Records were scrutinized to identify the development of HF, defined as signs and symptoms consistent with that diagnosis and treated with loop diuretics. HF was considered to have resolved if diuretics could be stopped without recurrent symptoms. Totally, 896 patients were identified of whom 54% had died by December 2005. During the index admission, 199 (22.2%) patients died, many with HF, and a further 182 (20.3%) patients developed HF that persisted until discharge, of whom 121 died subsequent to discharge. Of 74 patients with transient HF that resolved before discharge, 41 had recurrent HF and 38 died during follow-up. After discharge, 145 (33%) patients developed HF for the first time, of whom 76 died during follow-up. Overall, of 281 deaths occurring after discharge, 235 (83.6%) were amongst inpatients who first developed HF.

Conclusion: The development of HF precedes death in most patients who die in the short- or long-term following an MI. Prevention of HF, predominantly by reducing the extent of myocardial damage and recurrent MI, and subsequent management could have a substantial impact on prognosis.
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http://dx.doi.org/10.1093/eurheartj/ehn096DOI Listing
April 2008

Prevalence of ECG abnormalities in an international survey of patients with suspected or confirmed heart failure at death or discharge.

Eur J Heart Fail 2007 May 9;9(5):491-501. Epub 2007 Jan 9.

University of Hull, Kingston upon Hull, United Kingdom.

Background: Most patients suspected of having heart failure (HF) will get a 12-lead electrocardiogram (ECG) but its utility for excluding HF or assisting in its management has rarely been investigated.

Methods: The EuroHeart Failure survey identified 11,327 patients hospitalised with a suspected diagnosis of HF from 115 hospitals in 24 countries. ECGs were obtained from 9315 patients, of whom 5934 had cardiac imaging tests. The utility of the ECG was assessed for excluding or diagnosing major structural heart disease (MSHD) or major left ventricular systolic dysfunction (MLVSD) and for therapeutic decision making.

Findings: MSHD was present in 70% and MLVSD in 54% of patients overall but in only 21% and 5%, respectively, if the ECG was entirely normal. However, <2% of patients had a normal ECG. No single ECG characteristic identified a probability <25% of MSHD or <20% of MLVSD. Patients with QRS width >or=120 ms or anterior pathological Q-waves had a probability >80% of MSHD and >70% of MLVSD. Diagnostic models suggested that electrocardiographic criteria alone were not accurate for the diagnosis or exclusion of important heart disease in this population. However, 2468 patients (42%) had an electrocardiographic finding that should be used to guide the choice of therapy.

Conclusions: A normal ECG is rare in patients with suspected HF but has limited diagnostic value in this setting. The ECG has an important role in guiding therapy.
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http://dx.doi.org/10.1016/j.ejheart.2006.11.003DOI Listing
May 2007

How many patients need cardiac resynchronization therapy?

Eur Heart J 2006 Feb 7;27(3):251-2. Epub 2005 Dec 7.

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http://dx.doi.org/10.1093/eurheartj/ehi678DOI Listing
February 2006
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