Publications by authors named "Ellen Zhang"

18 Publications

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Book Club.

Authors:
Ellen Zhang

JAMA Oncol 2021 Apr;7(4):640

Harvard College, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamaoncol.2020.8014DOI Listing
April 2021

A Mouse Model to Investigate the Role of Cancer-associated Fibroblasts in Tumor Growth.

J Vis Exp 2020 12 22(166). Epub 2020 Dec 22.

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles; Molecular Biology Institute, University of California, Los Angeles;

Cancer-associated fibroblasts (CAFs) can play an important role in tumor growth by creating a tumor-promoting microenvironment. Models to study the role of CAFs in the tumor microenvironment can be helpful for understanding the functional importance of fibroblasts, fibroblasts from different tissues, and specific genetic factors in fibroblasts. Mouse models are essential for understanding the contributors to tumor growth and progression in an in vivo context. Here, a protocol in which cancer cells are mixed with fibroblasts and introduced into mice to develop tumors is provided. Tumor sizes over time and final tumor weights are determined and compared among groups. The protocol described can provide more insight into the functional role of CAFs in tumor growth and progression.
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http://dx.doi.org/10.3791/61883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238354PMC
December 2020

For the Necessary: You.

Authors:
Ellen Zhang

JAMA Oncol 2021 Feb;7(2):313

Harvard College, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamaoncol.2020.6190DOI Listing
February 2021

Delirium in Older Patients With COVID-19 Presenting to the Emergency Department.

JAMA Netw Open 2020 11 2;3(11):e2029540. Epub 2020 Nov 2.

Aging Brain Center, Marcus Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts.

Importance: Delirium is common among older emergency department (ED) patients, is associated with high morbidity and mortality, and frequently goes unrecognized. Anecdotal evidence has described atypical presentations of coronavirus disease 2019 (COVID-19) in older adults; however, the frequency of and outcomes associated with delirium in older ED patients with COVID-19 infection have not been well described.

Objective: To determine how frequently older adults with COVID-19 present to the ED with delirium and their associated hospital outcomes.

Design, Setting, And Participants: This multicenter cohort study was conducted at 7 sites in the US. Participants included consecutive older adults with COVID-19 presenting to the ED on or after March 13, 2020.

Exposure: COVID-19 was diagnosed by positive nasal swab for severe acute respiratory syndrome coronavirus 2 (99% of cases) or classic radiological findings (1% of cases).

Main Outcomes And Measures: The primary outcome was delirium as identified from the medical record according to a validated record review approach.

Results: A total of 817 older patients with COVID-19 were included, of whom 386 (47%) were male, 493 (62%) were White, 215 (27%) were Black, and 54 (7%) were Hispanic or Latinx. The mean (SD) age of patients was 77.7 (8.2) years. Of included patients, 226 (28%) had delirium at presentation, and delirium was the sixth most common of all presenting symptoms and signs. Among the patients with delirium, 37 (16%) had delirium as a primary symptom and 84 (37%) had no typical COVID-19 symptoms or signs, such as fever or shortness of breath. Factors associated with delirium were age older than 75 years (adjusted relative risk [aRR], 1.51; 95% CI, 1.17-1.95), living in a nursing home or assisted living (aRR, 1.23; 95% CI, 0.98-1.55), prior use of psychoactive medication (aRR, 1.42; 95% CI, 1.11-1.81), vision impairment (aRR, 1.98; 95% CI, 1.54-2.54), hearing impairment (aRR, 1.10; 95% CI 0.78-1.55), stroke (aRR, 1.47; 95% CI, 1.15-1.88), and Parkinson disease (aRR, 1.88; 95% CI, 1.30-2.58). Delirium was associated with intensive care unit stay (aRR, 1.67; 95% CI, 1.30-2.15) and death (aRR, 1.24; 95% CI, 1.00-1.55).

Conclusions And Relevance: In this cohort study of 817 older adults with COVID-19 presenting to US emergency departments, delirium was common and often was seen without other typical symptoms or signs. In addition, delirium was associated with poor hospital outcomes and death. These findings suggest the clinical importance of including delirium on checklists of presenting signs and symptoms of COVID-19 that guide screening, testing, and evaluation.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.29540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677760PMC
November 2020

Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans.

Am J Respir Crit Care Med 2021 02;203(4):424-436

Department of Internal Medicine, Center for Individualized and Genomic Medicine Research and.

The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants. To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals. We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) ( = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) ( = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) ( = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant. The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms. A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.
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http://dx.doi.org/10.1164/rccm.202006-2623OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885840PMC
February 2021

Before Chemotherapy.

Authors:
Ellen Zhang

J Med Humanit 2020 Dec;41(4):613

Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1007/s10912-020-09660-4DOI Listing
December 2020

Higher urate in LRRK2 mutation carriers resistant to Parkinson disease.

Ann Neurol 2019 04 3;85(4):593-599. Epub 2019 Mar 3.

Department of Neurology, Massachusetts General Hospital.

Objective: LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers.

Methods: Banked plasma samples or urate levels were obtained for 3 cohorts of age- and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex.

Results: Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p < 0.001), with similar results for separate assessments of women (p < 0.02) and men (p < 0.001). A 2 mg/dL increment in urate concentration decreased the odds of having PD by approximately 50% (odds ratio = 0.48, p = 0.004).

Interpretation: These findings identify and substantiate urate as a biomarker of resistance to PD among LRRK2 mutation carriers. Ann Neurol 2019;85:593-599.
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http://dx.doi.org/10.1002/ana.25436DOI Listing
April 2019

How does race and ethnicity effect the precision treatment of asthma?

Expert Rev Precis Med Drug Dev 2019 14;4(6):337-356. Epub 2019 Nov 14.

Center for Individualized and Genomic Medicine Research (CIGMA), Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.

Introduction: Asthma is a common condition that affects large numbers of children and adults, yet the burden of disease is not equally distributed amongst groups. In the United States, African Americans and Puerto Ricans have higher rates of asthma and its complications when compared with European Americans. However, clinical trials and genetic studies have largely focused on the latter group.

Areas Covered: Here we examine what is known regarding differences in asthma treatment response by race-ethnicity. We also review existing genetic studies related to the use of asthma medications, paying special attention to studies that included substantial numbers of non-white population groups. Publicly accessible search engines of the medical literature were queried using combinations of the terms asthma, race, ethnicity, pharmacogenomics, and pharmacogenetics, as well as the names of individual asthma medication classes. The list of articles reviewed was supplemented by bibliographies and expert knowledge.

Expert Opinion: A substantial and coordinated effort is still needed to both identify and validate genetic biomarkers of asthma medication response, as currently there are no clinically actionable genetic markers available for this purpose. The path to identifying such markers in non-white populations is even more formidable, since these groups are underrepresented in existing data.
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http://dx.doi.org/10.1080/23808993.2019.1690396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531627PMC
November 2019

Adipocyte arrestin domain-containing 3 protein (Arrdc3) regulates uncoupling protein 1 (Ucp1) expression in white adipose independently of canonical changes in β-adrenergic receptor signaling.

PLoS One 2017 14;12(3):e0173823. Epub 2017 Mar 14.

Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America.

Adaptive thermogenesis and cold-induced activation of uncoupling protein 1 (Ucp1) in brown adipose tissue in rodents is well-described and attributed to sympathetic activation of β-adrenergic signaling. The arrestin domain containing protein Arrdc3 is a regulator of obesity in mice and also appears linked to obesity in humans. We generated a mouse with conditional deletion of Arrdc3, and here we present evidence that genetic ablation of Arrdc3 specifically in adipocytes results in increased Ucp1 expression in subcutaneous and parametrial adipose tissue. Although this increase in expression did not correspond with significant changes in body weight or energy expenditure, adipocyte-specific Arrdc3-null mice had improved glucose tolerance. It was previously hypothesized that Arrdc3 ablation leads to increased β-adrenergic receptor sensitivity; however, in vitro experiments show that Arrdc3-null adipocytes responded to β-adrenergic receptor agonist with decreased Ucp1 levels. Additionally, canonical β-adrenergic receptor signaling was not different in Arrdc3-null adipocytes. These data reveal a role for Arrdc3 in the regulation of Ucp1 expression in adipocytes. However, this adipocyte effect is insufficient to generate the obesity-resistant phenotype of mice with ubiquitous deletion of Arrdc3, indicating a likely role for Arrdc3 in cells other than adipocytes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173823PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349670PMC
September 2017

4D Graph-Based Segmentation for Reproducible and Sensitive Choroid Quantification From Longitudinal OCT Scans.

Invest Ophthalmol Vis Sci 2016 07;57(9):OCT621-OCT630

Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, Iowa, United States 2Iowa Institute for Biomedical Imaging, The University of Iowa, Iowa City, Iowa, United States.

Purpose: Longitudinal imaging is becoming more commonplace for studies of disease progression, response to treatment, and healthy maturation. Accurate and reproducible quantification methods are desirable to fully mine the wealth of data in such datasets. However, most current retinal OCT segmentation methods are cross-sectional and fail to leverage the inherent context present in longitudinal sequences of images.

Methods: We propose a novel graph-based method for segmentation of multiple three-dimensional (3D) scans over time (termed 3D + time or 4D). The usefulness of this approach in retinal imaging is illustrated in the segmentation of the choroidal surfaces from longitudinal optical coherence tomography (OCT) scans. A total of 3219 synthetic (3070) and patient (149) OCT images were segmented for validation of our approach.

Results: The results show that the proposed 4D segmentation method is significantly more reproducible (P < 0.001) than the 3D approach and is significantly more sensitive to temporal changes (P < 0.0001) achieved by the substantial increase of measurement robustness.

Conclusions: This is the first automated 4D method for jointly quantifying choroidal thickness in longitudinal OCT studies. Our method is robust to image noise and produces more reproducible choroidal thickness measurements than a sequence of independent 3D segmentations, without sacrificing sensitivity to temporal changes.
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http://dx.doi.org/10.1167/iovs.15-18924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215413PMC
July 2016

Reactive oxygen species and bacterial biofilms in diabetic wound healing.

Physiol Genomics 2016 12 7;48(12):889-896. Epub 2016 Oct 7.

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California; and

Chronic wounds are a common and debilitating complication for the diabetic population. It is challenging to study the development of chronic wounds in human patients; by the time it is clear that a wound is chronic, the early phases of wound healing have passed and can no longer be studied. Because of this limitation, mouse models have been employed to better understand the early phases of chronic wound formation. In the past few years, a series of reports have highlighted the importance of reactive oxygen species and bacterial biofilms in the development of chronic wounds in diabetics. We review these recent findings and discuss mouse models that are being utilized to enhance our understanding of these potentially important contributors to chronic wound formation in diabetic patients.
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http://dx.doi.org/10.1152/physiolgenomics.00066.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206388PMC
December 2016

Compensation of spectral and RF errors in swept-source OCT for high extinction complex demodulation.

Opt Express 2015 Mar;23(5):5508-20

We provide a framework for compensating errors within passive optical quadrature demodulation circuits used in swept-source optical coherence tomography (OCT). Quadrature demodulation allows for detection of both the real and imaginary components of an interference fringe, and this information separates signals from positive and negative depth spaces. To achieve a high extinction (∼60 dB) between these positive and negative signals, the demodulation error must be less than 0.1% in amplitude and phase. It is difficult to construct a system that achieves this low error across the wide spectral and RF bandwidths of high-speed swept-source systems. In a prior work, post-processing methods for removing residual spectral errors were described. Here, we identify the importance of a second class of errors originating in the RF domain, and present a comprehensive framework for compensating both spectral and RF errors. Using this framework, extinctions >60 dB are demonstrated. A stability analysis shows that calibration parameters associated with RF errors are accurate for many days, while those associated with spectral errors must be updated prior to each imaging session. Empirical procedures to derive both RF and spectral calibration parameters simultaneously and to update spectral calibration parameters are presented. These algorithms provide the basis for using passive optical quadrature demodulation circuits with high speed and wide-bandwidth swept-source OCT systems.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394752PMC
http://dx.doi.org/10.1364/OE.23.005508DOI Listing
March 2015

Spectral binning for mitigation of polarization mode dispersion artifacts in catheter-based optical frequency domain imaging.

Opt Express 2013 Jul;21(14):16353-69

Wellman Center for Photomedicine, Harvard Medical School and Massachusetts General Hospital, 40 Blossom Street, Boston, Massachusetts 02114, USA.

Polarization mode dispersion (PMD) has been recognized as a significant barrier to sensitive and reproducible birefringence measurements with fiber-based, polarization-sensitive optical coherence tomography systems. Here, we present a signal processing strategy that reconstructs the local retardation robustly in the presence of system PMD. The algorithm uses a spectral binning approach to limit the detrimental impact of system PMD and benefits from the final averaging of the PMD-corrected retardation vectors of the spectral bins. The algorithm was validated with numerical simulations and experimental measurements of a rubber phantom. When applied to the imaging of human cadaveric coronary arteries, the algorithm was found to yield a substantial improvement in the reconstructed birefringence maps.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724396PMC
http://dx.doi.org/10.1364/OE.21.016353DOI Listing
July 2013

Combined reflectance confocal microscopy/optical coherence tomography imaging for skin burn assessment.

Biomed Opt Express 2013 May 8;4(5):680-95. Epub 2013 Apr 8.

Physical Sciences, Inc., Andover, MA 01810, USA.

A combined high-resolution reflectance confocal microscopy (RCM)/optical coherence tomography (OCT) instrument for assessing skin burn gravity has been built and tested. This instruments allows for visualizing skin intracellular details with submicron resolution in the RCM mode and morphological and birefringence modifications to depths on the order of 1.2 mm in the OCT mode. Preliminary testing of the dual modality imaging approach has been performed on the skin of volunteers with some burn scars and on normal and thermally-injured Epiderm FTTM skin constructs. The initial results show that these two optical technologies have complementary capabilities that can offer the clinician a set of clinically comprehensive parameters: OCT helps to visualize deeper burn injuries and possibly quantify collagen destruction by measuring skin birefringence, while RCM provides submicron details of the integrity of the epidermal layer and identifies the presence of the superficial blood flow in the upper dermis. Therefore, the combination of these two technologies within the same instrument may provide a more comprehensive set of parameters that may help clinicians to more objectively and nonivasively assess burn injury gravity by determining tissue structural integrity and viability.
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http://dx.doi.org/10.1364/BOE.4.000680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646596PMC
May 2013

Artifacts in polarization-sensitive optical coherence tomography caused by polarization mode dispersion.

Opt Lett 2013 Mar;38(6):923-5

Wellman Center for Photomedicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Polarization mode dispersion (PMD) severely degrades images of biological tissue measured with polarization-sensitive optical coherence tomography. It adds a bias to the local retardation value that can be spatially confined, resulting in regions of seemingly high sample birefringence that are purely artificial. Here, we demonstrate and analyze this effect, both experimentally and with numerical simulations, and show that artifacts can be avoided by limiting the system PMD to less than the system axial resolution. Even then, spatial averaging over a dimension larger than that characteristic of speckle is required to remove a PMD-induced bias of the local retardation values.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657722PMC
http://dx.doi.org/10.1364/OL.38.000923DOI Listing
March 2013

Numerical compensation of system polarization mode dispersion in polarization-sensitive optical coherence tomography.

Opt Express 2013 Jan;21(1):1163-80

Wellman Center for Photomedicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Polarization mode dispersion (PMD), which can be induced by circulators or even moderate lengths of optical fiber, is known to be a dominant source of instrumentation noise in fiber-based PS-OCT systems. In this paper we propose a novel PMD compensation method that measures system PMD using three fixed calibration signals, numerically corrects for these instrument effects and reconstructs an improved sample image. Using a frequency multiplexed PS-OFDI setup, we validate the proposed method by comparing birefringence noise in images of intralipid, muscle, and tendon with and without PMD compensation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636758PMC
http://dx.doi.org/10.1364/OE.21.001163DOI Listing
January 2013

Polarimetry noise in fiber-based optical coherence tomography instrumentation.

Opt Express 2011 Aug;19(18):16830-42

Wellman Center for Photomedicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

High noise levels in fiber-based polarization-sensitive optical coherence tomography (PS-OCT) have broadly limited its clinical utility. In this study we investigate contribution of polarization mode dispersion (PMD) to the polarimetry noise. We develop numerical models of the PS-OCT system including PMD and validate these models with empirical data. Using these models, we provide a framework for predicting noise levels, for processing signals to reduce noise, and for designing an optimized system.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482896PMC
http://dx.doi.org/10.1364/OE.19.016830DOI Listing
August 2011
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