Publications by authors named "Brian Li"

36 Publications

Enhanced Written vs. Verbal Recall Accuracy Associated With Greater Prefrontal Activation: A Near-Infrared Spectroscopy Study.

Front Behav Neurosci 2021 30;15:601698. Epub 2021 Mar 30.

Department of Rehabilitation Medicine, Third Affiliated Hospital of Soochow University, Changzhou, China.

Memory efficiency is influenced by the modalities of acquisition and retrieval. The recall accuracy of read or voiced material differs depending on whether the recall is given verbally or in writing. The medial prefrontal cortex (mPFC) is critical for both attentional allocation and short-term memory, suggesting that different short-term memory recall modalities are associated with distinct mPFC processes and activation patterns. Near-infrared spectroscopy (NIRS) was used to monitor mPFC oxygenation parameters of 30 healthy subjects during acquisition and recall tasks as a measure of neural activity. Oxygenation parameters and recall accuracy were compared between oral and written answers and the potential correlations were analyzed. Written responses were more accurate than verbal responses to the same questions and evoked greater changes in mPFC oxyhemoglobin (oxyHb) and total Hb (total-Hb). Furthermore, there were significant positive correlations between recall accuracy and both Δ[oxyHb] and Δ[total-Hb] in the mPFC. Memory accuracy of written material is greater when responses are also written rather than verbal. In both cases, recall accuracy was correlated with the degree of mPFC activity. This NIRS-based learning and memory paradigm may be useful for monitoring training efficacy, such as in patients with cognitive impairment.
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http://dx.doi.org/10.3389/fnbeh.2021.601698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042156PMC
March 2021

Utility of MyHEARTSMAP in Youth Presenting to the Emergency Room with Mental Health Concerns.

J Pediatr 2021 Apr 2. Epub 2021 Apr 2.

Department of Pediatrics, University of British Columbia, Vancouver, British Columbia. Electronic address:

Objectives: To evaluate the utility of a digital psychological self-assessment tool, MyHEARTSMAP, in youth presenting to the pediatric emergency department (ED) with a mental health concern.

Study Design: We conducted a prospective cohort study in two tertiary care pediatric EDs from December 2017-October 2019. Youth 10-17 years old triaged for a mental health concern were screened and enrolled to complete MyHEARTSMAP on a mobile device. A clinician blinded to the MyHEARTSMAP assessment conducted their own assessment which was used as the reference standard. Utility was quantified as the sensitivity and specificity of MyHEARTSMAP in detecting psychiatric, social, youth health, and functional concerns.

Results: Among 379 eligible youth, 351 were approached and 233 (66.4%) families were enrolled. Sensitivity for youth MyHEARTSMAP self-assessments ranged from 87.4% in the youth health domain to 99.5% in the psychiatric domain for identifying any concern, and 33.3% in the social domain to 74.6% in the psychiatric domain for severe concerns. Specificity ranged from 66.7% in the psychiatric domain to 98.2% in the youth health domain for no or only mild concerns.

Conclusion: Youth and guardian MyHEARTSMAP assessments are sensitive for detecting psychosocial concerns requiring follow-up beyond pediatric ED evaluation. Specificity for no or only mild concerns was high in the non-psychiatric domains.
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http://dx.doi.org/10.1016/j.jpeds.2021.03.062DOI Listing
April 2021

Biomarkers for the Diagnosis of Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis: A Systematic Review and Meta-Analysis.

J Allergy Clin Immunol Pract 2021 May 14;9(5):1909-1930.e4. Epub 2021 Jan 14.

Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus and impacts 10% of individuals with cystic fibrosis (CF). A diagnosis of ABPA is challenging to establish in CF owing to overlapping clinical and radiologic features with CF lung disease. Recent studies have identified blood tests, imaging, and other biomarkers that may be useful for diagnosis.

Objective: To summarize biomarkers that can aid in the diagnosis of ABPA in CF patients and to quantify their diagnostic accuracy through meta-analysis.

Methods: We searched MEDLINE, EMBASE, and the Cochrane Controlled Register of Trials and included studies that used a laboratory technique or imaging modality in CF patients diagnosed with ABPA. Pooled sensitivity and specificity were calculated using a hierarchical summary receiver operating characteristic model.

Results: We identified 791 articles, of which 29 met our eligibility criteria and 9 were included in the meta-analysis. Hyperattenuating mucus on computed tomography (CT) scan (n = 3 studies; pooled sensitivity 62% and specificity 92%) and serum specific immunoglobulin E against recombinant Aspergillus funigatus antigens f4 (n = 6; 69%, 89%) and f6 (n = 6; 39%, 97%) demonstrated high specificity. Based on single studies, serum thymus and activation regulated chemokine (92%, 94%), stimulated basophil expression of CD203c (94%, 74%), the inverted mucoid impaction signal on magnetic resonance imaging (94%, 100%), and skin prick test with recombinant Aspergillus fumigatus f4 and/or f6 (100%, 100%) showed high sensitivity and specificity.

Conclusions: Recent studies have found promising biomarkers for diagnosing ABPA in CF. Further research is needed to improve our understanding of their utility in diagnosis and disease monitoring.
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http://dx.doi.org/10.1016/j.jaip.2020.12.064DOI Listing
May 2021

National and Institutional Trends in Adverse Events Over Time: A Systematic Review and Meta-analysis of Longitudinal Retrospective Patient Record Review Studies.

J Patient Saf 2021 03;17(2):141-148

Division of Population Health Science, Department of Epidemiology and Public Health.

Objective: This study aimed to determine if the implementation of large-scale patient safety initiatives have been successful in reducing overall and preventable adverse event rates in hospital inpatients.

Design: The design used in this study was systematic review and meta-analysis.

Data Resources: We followed our published protocol (PROSPERO [CRD42019140058]) and searched the following databases: PubMed, CINAHL, PsycINFO, Cochrane Library, and Embase from inception to February 2020. The reference lists of eligible studies were also searched.

Eligibility: All longitudinal retrospective record review studies that examined adverse event rates before and after the introduction of patient safety initiatives in hospital inpatients were included.

Data Extraction: Data extraction, quality, and risk of bias assessment were carried out by 2 independent reviewers. Information on study design, setting, demographics, interventions, and safety outcome measures was extracted.

Results: A total of 3894 articles were screened, and 7 articles met the eligibility criteria for our systematic review with 5 of these providing sufficient information for inclusion in the meta-analysis. The degree of heterogeneity was high among studies. The meta-analysis demonstrated a minimal risk reduction in overall adverse event rates of 0.017 (95% confidence interval, 0.002-0.032) when the lower-quality studies were excluded, with one adverse event being prevented for every 59 hospital admissions.

Conclusions: These findings are significant when the large numbers of admissions to a hospital every year are considered. Given the low numbers of large-scale implementation studies, there is a need for more research on the effectiveness of patient safety initiatives to further assess the impact of such initiatives on adverse events.
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http://dx.doi.org/10.1097/PTS.0000000000000804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908854PMC
March 2021

High Rates of Mortality in Geriatric Patients Admitted for Inflammatory Bowel Disease Management.

J Clin Gastroenterol 2020 Nov 23. Epub 2020 Nov 23.

Department of Internal Medicine.

Goal: The goal of this study was to evaluate the inpatient mortality risk among geriatric patients with inflammatory bowel disease (IBD).

Background: The challenges of caring for elderly patients with IBD will increase with the aging of the US population. Given the complications of hospitalization, we set to examine if elderly patients age older than 65 were at higher risk of mortality.

Materials And Methods: All patients with ulcerative colitis (UC) or Crohn's disease (CD) in the National Inpatient Sample (NIS) from 2016 and 2017 as the primary diagnosis or secondary diagnosis with an IBD-related cause of admission were included. Outcomes for patients aged above 65 were compared with below 65 using multivariable survey-adjusted regression. CD and UC were analyzed separately.

Results: In 2016-2017, there were an estimated 162,800 admissions for CD and related complications compared with 96,450 for UC. In total, 30% of UC and 20% of CD admissions were geriatric. Geriatric status was associated with higher odds of mortality for CD [odds ratio (OR)=3.47, 95% confidence interval (CI): 2.72-4.44] and UC (OR=2.75, 95% CI: 2.16-3.49) after adjustment for comorbidities, admission type, hospital type, inpatient surgery, and IBD subtype. The cause of death was ∼80% infectious in both CD and UC in all groups. An average of 0.19 days (95% CI: 0.05-0.34) and $2467 (95% CI: 545-4388) increase was seen for geriatric CD patients. No significant change was seen for UC.

Conclusions: Age over 65 was independently associated with higher odds of death in both UC and CD patients, even after appropriate adjustment. Further research is needed to optimize care for this growing patient population.
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http://dx.doi.org/10.1097/MCG.0000000000001458DOI Listing
November 2020

Evidence for treatment of lower limb in-stent restenosis with drug eluting balloons.

J Cardiovasc Surg (Torino) 2020 10;61(5):626-631

Division of Vascular and Endovascular Surgery, Department of Surgery, Queen Mary Hospital, University of Hong Kong Medical Centre, Hong Kong, China.

Introduction: Restenosis by myointimal hyperplasia after peripheral arterial angioplasty or stenting often limits long term patency. Drug-eluting balloons (DEBs) which inhibit the proliferation of neo-intimal growth of vascular smooth muscle cells may prevent restenosis. The aim of this paper was to examine the evidence in published literature on the use of DEBs in the treatment of peripheral arterial in-stent restenosis (ISR).

Evidence Acquisition: A systematic literature review was undertaken of all published literature on the treatment of peripheral ISR with drug eluting balloon using Medline and cross-referenced. All published papers on the use of DEBs in peripheral arterial disease (PAD) were used. Cochrane Central Register of Controlled Trials and electronic databases were also searched for on-going studies.

Evidence Synthesis: There were no level 1 or 2 evidence published on this subject. The number of high-quality publications is few, and consequently a sufficient analysis is not possible. Recently data from non-randomized cohort studies showed encouraging results with DEB as treatment modality for ISR, whether used alone or as combined strategies.

Conclusions: Evidence from the published literature suggests that DEBs are safe in preventing peripheral ISR. Despite strong corporate pressure for the use of DEBs, there is only circumstantial evidence that this is a useful modality for ISR. Results from on-going studies may allow further meta-analysis for efficiency and cost-effectiveness.
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October 2020

Response.

Gastrointest Endosc 2020 11;92(5):1140-1141

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA.

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http://dx.doi.org/10.1016/j.gie.2020.07.014DOI Listing
November 2020

A Review of the Applications, Environmental Release, and Remediation Technologies of Per- and Polyfluoroalkyl Substances.

Int J Environ Res Public Health 2020 11 3;17(21). Epub 2020 Nov 3.

Department of Chemical and Material Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA.

Per- and polyfluoroalkyl substances (PFAS) are pollutants that have demonstrated a high level of environmental persistence and are very difficult to remediate. As the body of literature on their environmental effects has increased, so has regulatory and research scrutiny. The widespread usage of PFAS in industrial applications and consumer products, complicated by their environmental release, mobility, fate, and transport, have resulted in multiple exposure routes for humans. Furthermore, low screening levels and stringent regulatory standards that vary by state introduce considerable uncertainty and potential costs in the environmental management of PFAS. The recalcitrant nature of PFAS render their removal difficult, but existing and emerging technologies can be leveraged to destroy or sequester PFAS in a variety of environmental matrices. Additionally, new research on PFAS remediation technologies has emerged to address the efficiency, costs, and other shortcomings of existing remediation methods. Further research on the impact of field parameters such as secondary water quality effects, the presence of co-contaminants and emerging PFAS, reaction mechanisms, defluorination yields, and the decomposition products of treatment technologies is needed to fully evaluate these emerging technologies, and industry attention should focus on treatment train approaches to improve efficiency and reduce the cost of treatment.
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http://dx.doi.org/10.3390/ijerph17218117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663283PMC
November 2020

Amniotic membrane harvesting during COVID-19 pandemic.

Eye (Lond) 2021 03 12;35(3):1019. Epub 2020 May 12.

Department of Ophthalmology, United Christian Hospital, Hong Kong, Hong Kong.

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http://dx.doi.org/10.1038/s41433-020-0947-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216571PMC
March 2021

Outcomes in lower GI bleeding comparing weekend with weekday admission.

Gastrointest Endosc 2020 Sep 21;92(3):675-680.e6. Epub 2020 Apr 21.

Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.

Background And Aims: Acute lower gastrointestinal bleeding (LGIB) is a common indication for hospitalization potentially requiring urgent intervention, which may not be readily available at weekends and off-hours. The aim of this study was to examine the association between weekend admission for LGIB and mortality, time to colonoscopy, length of stay, and hospital charges.

Methods: The 2016 U.S. National Inpatient Sample (NIS) dataset was queried for admissions with a primary diagnosis of LGIB. Outcomes for weekend versus weekday admissions were compared using survey-adjusted chi-squared or bivariate correlation. Multivariable regression was then used to compare primary outcomes adjusting for the Elixhauser mortality score (a validated measure of comorbidities), colonoscopy, transfusion, shock, and hospital type.

Results: An estimated 124,620 patients were admitted for LGIB in 2016. Comparing weekend with weekday admissions, there was no difference in unadjusted mortality (0.9% vs 1.0%, P = .636). Colonoscopy within the first day (28.6% vs 23.0%, P < .001) and transfusion (34.0% vs 31.5%, P < .001) were more common with weekday admissions; no differences in colonoscopy rate (60.7% vs 60.9%, P = .818), angiography rate (2.7% vs 2.7%, P = .976), mean days to colonoscopy (2.0 vs 2.0, P = .233), or length of stay (4.2 vs 4.1 days, P = .068) were seen. There was no difference in multivariable adjusted mortality rates (odds ratio, 1.11; 95% confidence interval, 0.81-1.54; P = .495) based on the above factors.

Conclusions: Early colonoscopy (within the first day) is more common for weekday admissions, but overall outcomes are not affected by weekend admission for LGIB compared with weekday admissions.
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http://dx.doi.org/10.1016/j.gie.2020.04.031DOI Listing
September 2020

Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer.

Sci Rep 2019 05 24;9(1):7826. Epub 2019 May 24.

The Vancouver Prostate Centre, Department of Urological Sciences, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia, V6H 3Z6, Canada.

Tunneling nanotubes (TNTs) are actin-based membranous structures bridging distant cells for intercellular communication. We define roles for TNTs in stress adaptation and treatment resistance in prostate cancer (PCa). Androgen receptor (AR) blockade and metabolic stress induce TNTs, but not in normal prostatic epithelial or osteoblast cells. Co-culture assays reveal enhanced TNT formation between stressed and unstressed PCa cells as well as from stressed PCa to osteoblasts. Stress-induced chaperones clusterin and YB-1 localize within TNTs, are transported bi-directionally via TNTs and facilitate TNT formation in PI3K/AKT and Eps8-dependent manner. AR variants, induced by AR antagonism to mediate resistance to AR pathway inhibition, also enhance TNT production and rescue loss of clusterin- or YB-1-repressed TNT formation. TNT disruption sensitizes PCa to treatment-induced cell death. These data define a mechanistic network involving stress induction of chaperone and AR variants, PI3K/AKT signaling, actin remodeling and TNT-mediated intercellular communication that confer stress adaptative cell survival.
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http://dx.doi.org/10.1038/s41598-019-44346-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534589PMC
May 2019

Symptom Assessment in Patients with Advanced Cancer: Are the Most Severe Symptoms the Most Bothersome?

J Palliat Med 2019 10 7;22(10):1252-1259. Epub 2019 May 7.

Department of Supportive Care, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

We investigated correspondence between symptom severity and symptom bothersomeness in patients with advanced cancer. Symptom severity is commonly assessed in clinical cancer settings, but bothersomeness of these symptoms is less often measured. Participants with advanced cancer enrolled in a cluster-randomized trial of early palliative care completed the Edmonton Symptom Assessment System (ESAS) and the quality of life at the end of life (QUAL-E) measure as part of their baseline assessment. For each symptom, we examined the correspondence between the symptom being indicated as most severe on the ESAS and rated as most bothersome on the QUAL-E. For the 386 patients who completed relevant sections of the ESAS and QUAL-E, tiredness (32.8%), sleep (23.8%), and appetite (20.2%) were most frequently rated as most severe, whereas pain (28.9%) and tiredness (24.3%) were most frequently indicated as most bothersome. The most bothersome and most severe symptom corresponded in 42%. Pain and/or tiredness were consistently among the top three most bothersome symptoms, whereas appetite was frequently rated the most severe symptom but was rarely perceived as the most bothersome. The probability that patients rating a symptom as most severe would also rate it as most bothersome was highest for pain (66%), nausea (58%), and tiredness (40%). ESAS symptom severity does not necessarily indicate patients' most bothersome symptom; regardless of severity, pain and tiredness are most frequently perceived as most bothersome. Further research should investigate the clinical benefits of patients also indicating their three most bothersome ESAS symptoms.
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http://dx.doi.org/10.1089/jpm.2018.0622DOI Listing
October 2019

Visco-Node-Pore Sensing: A Microfluidic Rheology Platform to Characterize Viscoelastic Properties of Epithelial Cells.

iScience 2019 Mar 27;13:214-228. Epub 2019 Feb 27.

Department of Mechanical Engineering, University of California at Berkeley, Berkeley, CA, USA; Graduate Program in Bioengineering, University of California, Berkeley, University of California, San Francisco, Berkeley, CA, USA. Electronic address:

Viscoelastic properties of cells provide valuable information regarding biological or clinically relevant cellular characteristics. Here, we introduce a new, electronic-based, microfluidic platform-visco-node-pore sensing (visco-NPS)-which quantifies cellular viscoelastic properties under periodic deformation. We measure the storage (G') and loss (G″) moduli (i.e., elasticity and viscosity, respectively) of cells. By applying a wide range of deformation frequencies, our platform quantifies the frequency dependence of viscoelastic properties. G' and G″ measurements show that the viscoelastic properties of malignant breast epithelial cells (MCF-7) are distinctly different from those of non-malignant breast epithelial cells (MCF-10A). With its sensitivity, visco-NPS can dissect the individual contributions of different cytoskeletal components to whole-cell mechanical properties. Moreover, visco-NPS can quantify the mechanical transitions of cells as they traverse the cell cycle or are initiated into an epithelial-mesenchymal transition. Visco-NPS identifies viscoelastic characteristics of cell populations, providing a biophysical understanding of cellular behavior and a potential for clinical applications.
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http://dx.doi.org/10.1016/j.isci.2019.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416673PMC
March 2019

Clonal expansion and compartmentalized maintenance of rhesus macaque NK cell subsets.

Sci Immunol 2018 11;3(29)

Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.

Natural killer (NK) cells recognize and eliminate infected and malignant cells. Their life histories are poorly understood, particularly in humans, due to lack of informative models and endogenous clonal markers. Here, we apply transplantation of barcoded rhesus macaque hematopoietic cells to interrogate the landscape of NK cell production, expansion, and life histories at a clonal level long term and after proliferative challenge. We identify oligoclonal populations of rhesus CD56CD16 NK cells that are characterized by marked expansions and contractions over time yet remained long-term clonally uncoupled from other hematopoietic lineages, including CD56CD16 NK cells. Individual or groups of CD56CD16 expanded clones segregated with surface expression of specific killer immunoglobulin-like receptors. These clonally distinct NK cell subpopulation patterns persisted for more than 4 years, including after transient in vivo anti-CD16-mediated depletion and subsequent regeneration. Profound and sustained interleukin-15-mediated depletion was required to generate new oligoclonal CD56CD16 NK cells. Together, our results indicate that linear NK cell production from multipotent hematopoietic progenitors or less mature CD56CD16 cells is negligible during homeostasis and moderate proliferative stress. In such settings, peripheral compartmentalized self-renewal can maintain the composition of distinct, differentiated NK cell subpopulations.
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http://dx.doi.org/10.1126/sciimmunol.aat9781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393805PMC
November 2018

A Review of the Processes, Parameters, and Optimization of Anaerobic Digestion.

Int J Environ Res Public Health 2018 10 11;15(10). Epub 2018 Oct 11.

The Pingry School, Basking Ridge, NJ 07920, USA.

Anaerobic digestion is a technology that has been used by humans for centuries. Anaerobic digestion is considered to be a useful tool that can generate renewable energy and significant research interest has arisen recently. The underlying theory of anaerobic digestion has been established for decades; however, a great deal of current research is directed towards the optimization of anaerobic digestion under diverse digestion conditions. This review provides a summary of the processes underlying anaerobic digestion, commonly-utilized measurements of anaerobic sludge, operating parameters of anaerobic digesters, and methods of acceleration and optimization used to improve process efficiency. Recent developments in addition to older research are considered to provide a general but comprehensive summary of accumulated knowledge in the theory of anaerobic digestion, as well as considerations in the efficient operation of digesters. We have determined that the numerous factors pertinent to the design and operation of batch-based anaerobic digesters must each be considered to ensure the maximum efficiency and cost-effectiveness of a digester provided its respective operating conditions.
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http://dx.doi.org/10.3390/ijerph15102224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210450PMC
October 2018

Generation of mouse-zebrafish hematopoietic tissue chimeric embryos for hematopoiesis and host-pathogen interaction studies.

Dis Model Mech 2018 11 5;11(11). Epub 2018 Nov 5.

Center for Genome Regulation, Facultad de Ciencias, Universidad de Chile, Santiago 8370415, Chile

Xenografts of the hematopoietic system are extremely useful as disease models and for translational research. Zebrafish xenografts have been widely used to monitor blood cancer cell dissemination and homing due to the optical clarity of embryos and larvae, which allow unrestricted visualization of migratory events. Here, we have developed a xenotransplantation technique that transiently generates hundreds of hematopoietic tissue chimeric embryos by transplanting murine bone marrow cells into zebrafish blastulae. In contrast to previous methods, this procedure allows mammalian cell integration into the fish developmental hematopoietic program, which results in chimeric animals containing distinct phenotypes of murine blood cells in both circulation and the hematopoietic niche. Murine cells in chimeric animals express antigens related to (i) hematopoietic stem and progenitor cells, (ii) active cell proliferation and (iii) myeloid cell lineages. We verified the utility of this method by monitoring zebrafish chimeras during development using non-invasive imaging to show novel murine cell behaviors, such as homing to primitive and definitive hematopoietic tissues, dynamic hematopoietic cell and hematopoietic niche interactions, and response to bacterial infection. Overall, transplantation into the zebrafish blastula provides a useful method that simplifies the generation of numerous chimeric animals and expands the range of murine cell behaviors that can be studied in zebrafish chimeras. In addition, integration of murine cells into the host hematopoietic system during development suggests highly conserved molecular mechanisms of hematopoiesis between zebrafish and mammals.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.034876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262816PMC
November 2018

Droplet digital PCR shows the D-Loop to be an error prone locus for mitochondrial DNA copy number determination.

Sci Rep 2018 07 30;8(1):11392. Epub 2018 Jul 30.

Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, Canada.

Absolute quantification of mitochondrial DNA copy number (mCN) provides important insights in many fields of research including cancer, cardiovascular and reproductive health. Droplet digital PCR (ddPCR) natively reports absolute copy number, and we have developed a single-dye, multiplex assay to measure rat mCN that is accurate, precise and affordable. We demonstrate simple methods to optimize this assay and to determine nuclear reference pseudogene copy number to extend the range of mCN that can be measured with this assay. We evaluated two commonly used mitochondrial DNA reference loci to determine mCN, the ND1 gene and the D-Loop. Harnessing the absolute measures of ddPCR, we found that the D-Loop amplifies with a copy number of ~1.0-1.5 relative to other sites on the mitochondrial genome. This anomalous copy number varied significantly between rats and tissues (aorta, brain, heart, liver, soleus muscle). We advocate for avoiding the D-Loop as a mitochondrial reference in future studies of mCN. Further, we report a novel approach to quantifying immunolabelled mitochondrial DNA that provides single-cell estimates of mCN that closely agree with the population analyses by ddPCR. The combination of these assays represents a cost-effective and powerful suite of tools to study mCN.
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http://dx.doi.org/10.1038/s41598-018-29621-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065360PMC
July 2018

Developments in label-free microfluidic methods for single-cell analysis and sorting.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2019 01 24;11(1):e1529. Epub 2018 Apr 24.

UC Berkeley-UC San Francisco Graduate Program in Bioengineering, University of California, Berkeley Graduate Division, Berkeley, California.

Advancements in microfluidic technologies have led to the development of many new tools for both the characterization and sorting of single cells without the need for exogenous labels. Label-free microfluidics reduce the preparation time, reagents needed, and cost of conventional methods based on fluorescent or magnetic labels. Furthermore, these devices enable analysis of cell properties such as mechanical phenotype and dielectric parameters that cannot be characterized with traditional labels. Some of the most promising technologies for current and future development toward label-free, single-cell analysis and sorting include electronic sensors such as Coulter counters and electrical impedance cytometry; deformation analysis using optical traps and deformation cytometry; hydrodynamic sorting such as deterministic lateral displacement, inertial focusing, and microvortex trapping; and acoustic sorting using traveling or standing surface acoustic waves. These label-free microfluidic methods have been used to screen, sort, and analyze cells for a wide range of biomedical and clinical applications, including cell cycle monitoring, rapid complete blood counts, cancer diagnosis, metastatic progression monitoring, HIV and parasite detection, circulating tumor cell isolation, and point-of-care diagnostics. Because of the versatility of label-free methods for characterization and sorting, the low-cost nature of microfluidics, and the rapid prototyping capabilities of modern microfabrication, we expect this class of technology to continue to be an area of high research interest going forward. New developments in this field will contribute to the ongoing paradigm shift in cell analysis and sorting technologies toward label-free microfluidic devices, enabling new capabilities in biomedical research tools as well as clinical diagnostics. This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > Diagnostic Nanodevices.
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http://dx.doi.org/10.1002/wnan.1529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200655PMC
January 2019

Impact of Interventional Oncology Therapies on Tumor Microenvironment and Strategies to Enhance Their Efficacy.

AJR Am J Roentgenol 2018 Mar 24;210(3):648-656. Epub 2018 Jan 24.

3 Department of Radiology, McMaster University Medical Center, 1200 Main St West, Hamilton, ON L8N 325, Canada.

Objective: We provide a brief review of the tumor microenvironment, the impact of six interventional radiology treatments on the tumor microenvironment, and potential methods to improve treatment efficacy.

Conclusion: Interventional oncology plays a unique role in cancer therapy, contributing to both antitumorigenic and protumorigenic effects.
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http://dx.doi.org/10.2214/AJR.16.17677DOI Listing
March 2018

Geographic clonal tracking in macaques provides insights into HSPC migration and differentiation.

J Exp Med 2018 01 15;215(1):217-232. Epub 2017 Nov 15.

Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.

The geographic distribution of hematopoiesis at a clonal level is of interest in understanding how hematopoietic stem and progenitor cells (HSPCs) and their progeny interact with bone marrow (BM) niches during regeneration. We tagged rhesus macaque autologous HSPCs with genetic barcodes, allowing clonal tracking over time and space after transplantation. We found marked geographic segregation of CD34 HSPCs for at least 6 mo posttransplantation, followed by very gradual clonal mixing at different BM sites over subsequent months to years. Clonal mapping was used to document local production of granulocytes, monocytes, B cells, and CD56 natural killer (NK) cells. In contrast, CD16CD56 NK cells were not produced in the BM, and in fact were clonally distinct from multipotent progenitors producing all other lineages. Most surprisingly, we documented local BM production of CD3 T cells early after transplantation, using both clonal mapping and intravascular versus tissue-resident T cell staining, suggesting a thymus-independent T cell developmental pathway operating during BM regeneration, perhaps before thymic recovery.
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http://dx.doi.org/10.1084/jem.20171341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748860PMC
January 2018

LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression.

Cancer Res 2017 10 15;77(20):5479-5490. Epub 2017 Sep 15.

Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada.

Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0496DOI Listing
October 2017

CXCR1 remodels the vascular niche to promote hematopoietic stem and progenitor cell engraftment.

J Exp Med 2017 04 28;214(4):1011-1027. Epub 2017 Mar 28.

Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA 02138

The microenvironment is an important regulator of hematopoietic stem and progenitor cell (HSPC) biology. Recent advances marking fluorescent HSPCs have allowed exquisite visualization of HSPCs in the caudal hematopoietic tissue (CHT) of the developing zebrafish. Here, we show that the chemokine and its receptor, , are expressed by zebrafish endothelial cells, and we identify signaling as a positive regulator of HSPC colonization. Single-cell tracking experiments demonstrated that this is a result of increases in HSPC-endothelial cell "cuddling," HSPC residency time within the CHT, and HSPC mitotic rate. Enhanced signaling was associated with an increase in the volume of the CHT and induction of expression. Finally, using parabiotic zebrafish, we show that acts HSPC nonautonomously to improve the efficiency of donor HSPC engraftment. This work identifies a mechanism by which the hematopoietic niche remodels to promote HSPC engraftment and suggests that signaling is a potential therapeutic target in patients undergoing hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1084/jem.20161616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379982PMC
April 2017

Quantitative stability of hematopoietic stem and progenitor cell clonal output in rhesus macaques receiving transplants.

Blood 2017 03 13;129(11):1448-1457. Epub 2017 Jan 13.

Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.

Autologous transplantation of hematopoietic stem and progenitor cells lentivirally labeled with unique oligonucleotide barcodes flanked by sequencing primer targets enables quantitative assessment of the self-renewal and differentiation patterns of these cells in a myeloablative rhesus macaque model. Compared with other approaches to clonal tracking, this approach is highly quantitative and reproducible. We documented stable multipotent long-term hematopoietic clonal output of monocytes, granulocytes, B cells, and T cells from a polyclonal pool of hematopoietic stem and progenitor cells in 4 macaques observed for up to 49 months posttransplantation. A broad range of clonal behaviors characterized by contribution level and biases toward certain cell types were extremely stable over time. Correlations between granulocyte and monocyte clonalities were greatest, followed by correlations between these cell types and B cells. We also detected quantitative expansion of T cell-biased clones consistent with an adaptive immune response. In contrast to recent data from a nonquantitative murine model, there was little evidence for clonal succession after initial hematopoietic reconstitution. These findings have important implications for human hematopoiesis, given the similarities between macaque and human physiologies.
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http://dx.doi.org/10.1182/blood-2016-07-728691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356453PMC
March 2017

Connectosomes for Direct Molecular Delivery to the Cellular Cytoplasm.

J Am Chem Soc 2016 10 26;138(39):12833-12840. Epub 2016 Sep 26.

Department of Biomedical Engineering, ‡College of Pharmacy, and §Institute for Cellular and Molecular Biology, The University of Texas at Austin , Austin, Texas 78712, United States.

Transport of biomolecules, drugs, and other reagents across the cell's plasma membrane barrier is an inefficient and poorly controlled process, despite its fundamental importance to biotechnology, cell biology, and pharmaceutics. In particular, insufficient membrane permeability frequently limits the accumulation of drugs and reagents in the cytoplasm, undermining their efficacy. While encapsulating drugs in particles increases uptake by cells, inefficient release of drugs from these particles into the cytoplasm ultimately limits drug efficacy. In contrast, gap junctions provide a direct route to the cytoplasm that bypasses the plasma membrane. As transmembrane channels that physically connect the cytoplasm of adjacent cells, gap junctions permit transport of a diverse range of molecules, from ions and metabolites to siRNA, peptides, and chemotherapeutics. To utilize gap junctions for molecular delivery we have developed Connectosomes, cell-derived lipid vesicles that contain functional gap junction channels and encapsulate molecular cargos. Here we show that these vesicles form gap junction channels with cells, opening a direct and efficient route for the delivery of molecular cargo to the cellular cytoplasm. Specifically, we demonstrate that using gap junctions to deliver the chemotherapeutic doxorubicin reduces the therapeutically effective dose of the drug by more than an order of magnitude. Delivering drugs through gap junctions has the potential to boost the effectiveness of existing drugs such as chemotherapeutics, while simultaneously enabling the delivery of membrane-impermeable drugs and reagents.
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http://dx.doi.org/10.1021/jacs.6b05191DOI Listing
October 2016

Generation of Parabiotic Zebrafish Embryos by Surgical Fusion of Developing Blastulae.

J Vis Exp 2016 06 11(112). Epub 2016 Jun 11.

Division of Hematology/Oncology, Boston Children's Hospital; Harvard Medical School; Division of Hematology, Department of Medicine, Brigham and Women's Hospital; Harvard Stem Cell Institute; Broad Institute of Massachusetts Institute of Technology;

Surgical parabiosis of two animals of different genetic backgrounds creates a unique scenario to study cell-intrinsic versus cell-extrinsic roles for candidate genes of interest, migratory behaviors of cells, and secreted signals in distinct genetic settings. Because parabiotic animals share a common circulation, any blood or blood-borne factor from one animal will be exchanged with its partner and vice versa. Thus, cells and molecular factors derived from one genetic background can be studied in the context of a second genetic background. Parabiosis of adult mice has been  used extensively to research aging, cancer, diabetes, obesity, and brain development. More recently, parabiosis of zebrafish embryos has been used to study the developmental biology of hematopoiesis. In contrast to mice, the transparent nature of zebrafish embryos permits the direct visualization of cells in the parabiotic context, making it a uniquely powerful method for investigating fundamental cellular and molecular mechanisms. The utility of this technique, however, is limited by a steep learning curve for generating the parabiotic zebrafish embryos. This protocol provides a step-by-step method on how to surgically fuse the blastulae of two zebrafish embryos of different genetic backgrounds to investigate the role of candidate genes of interest. In addition, the parabiotic zebrafish embryos are tolerant to heat shock, making temporal control of gene expression possible. This method does not require a sophisticated set-up and has broad applications for studying cell migration, fate specification, and differentiation in vivo during embryonic development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927786PMC
http://dx.doi.org/10.3791/54168DOI Listing
June 2016

The impact of physiological crowding on the diffusivity of membrane bound proteins.

Soft Matter 2016 Feb 11;12(7):2127-34. Epub 2016 Jan 11.

Department of Biomedical Engineering, The University of Texas at Austin, TX, Austin, USA.

Diffusion of transmembrane and peripheral membrane-bound proteins within the crowded cellular membrane environment is essential to diverse biological processes including cellular signaling, endocytosis, and motility. Nonetheless we presently lack a detailed understanding of the influence of physiological levels of crowding on membrane protein diffusion. Utilizing quantitative in vitro measurements, here we demonstrate that the diffusivities of membrane bound proteins follow a single linearly decreasing trend with increasing membrane coverage by proteins. This trend holds for homogenous protein populations across a range of protein sizes and for heterogeneous mixtures of proteins of different sizes, such that protein diffusivity is controlled by the total coverage of the surrounding membrane. These results demonstrate that steric exclusion within the crowded membrane environment can fundamentally limit the diffusive rate of proteins, regardless of their size. In cells this "speed limit" could be modulated by changes in local membrane coverage, providing a mechanism for tuning the rate of molecular interaction and assembly.
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http://dx.doi.org/10.1039/c5sm02572aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749440PMC
February 2016

Multiwalled Carbon Nanotubes at the Interface of Pickering Emulsions.

Langmuir 2015 Dec 24;31(48):13077-84. Epub 2015 Nov 24.

School of Chemical, Biological and Materials Engineering, University of Oklahoma , Norman, Oklahoma 73019, United States.

Carbon nanotubes exhibit very unique properties in biphasic systems. Their interparticle attraction leads to reduced droplet coalescence rates and corresponding improvements in emulsion stability. Here we use covalent and noncovalent techniques to modify the hydrophilicity of multiwalled carbon nanotubes (MWCNTs) and study their resulting behavior at an oil-water interface. By using both paraffin wax/water and dodecane/water systems, the thickness of the layer of MWNTs at the interface and resulting emulsion stability are shown to vary significantly with the approach used to modify the MWNTs. Increased hydrophilicity of the MWNTs shifts the emulsions from water-in-oil to oil-in-water. The stability of the emulsion is found to correlate with the thickness of nanotubes populating the oil-water interface and relative strength of the carbon nanotube network. The addition of a surfactant decreases the thickness of nanotubes at the interface and enhances the overall interfacial area stabilized at the expense of increased droplet coalescence rates. To the best of our knowledge, this is the first time the interfacial thickness of modified carbon nanotubes has been quantified and correlated to emulsion stability.
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http://dx.doi.org/10.1021/acs.langmuir.5b03189DOI Listing
December 2015

Identification and evaluation of network modules for the prognosis of basal-like breast cancer.

Oncotarget 2015 Jul;6(19):17713-24

Department of Oncology, McMaster University, Hamilton, Ontario, Canada.

Purpose: Basal-like breast cancer (BLBC) is a molecular subtype of breast cancer associated with poor clinical outcome, although some patients with BLBC experience long-term survival. Apart from nodal status, current clinical/histopathological variables show little capacity to identify BLBC patients at either high- or low-risk of disease recurrence. Accordingly, we sought to develop a network based genomic predictor for predicting the outcome of patients with BLBC.

Experimental Design: We performed network analysis on global gene expression profiling data of BLBCs, and identified BLBC network modules associated with AP-1 transcription, G-protein coupled receptors, and T-, B-, and NK-cells that are significant predictors of BLBC patient survival.

Results: In gene expression and tissue microarray (TMA) validation cohorts of 210 and 102 BLBC patients, respectively, the identified network modules were robustly associated with patient outcome. In the gene expression validation cohort, the Kaplan-Meier estimate for 10-year survival in the low-risk group was 90%, whereas in the high-risk group it was a 56%. In the TMA cohort, the Kaplan-Meier estimate for 10-year survival in the low-risk group was 98%, whereas in the high-risk group it was 71%.

Conclusions: The capacity to distinguish between patients with BLBC at high- or low-risk of recurrence at the time of diagnosis could permit timely intervention with more aggressive therapeutic regimens in those patients predicted to be high-risk, and to avoid such therapy in low-risk patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627340PMC
http://dx.doi.org/10.18632/oncotarget.4034DOI Listing
July 2015

Clonal tracking of rhesus macaque hematopoiesis highlights a distinct lineage origin for natural killer cells.

Cell Stem Cell 2014 Apr;14(4):486-499

Hematology Branch; National Heart, Lung and Blood Institute; National Institutes of Health, Bethesda, MD 20892, USA.

Analysis of hematopoietic stem cell function in nonhuman primates provides insights that are relevant for human biology and therapeutic strategies. In this study, we applied quantitative genetic barcoding to track the clonal output of transplanted autologous rhesus macaque hematopoietic stem and progenitor cells over a time period of up to 9.5 months. We found that unilineage short-term progenitors reconstituted myeloid and lymphoid lineages at 1 month but were supplanted over time by multilineage clones, initially myeloid restricted, then myeloid-B clones, and then stable myeloid-B-T multilineage, long-term repopulating clones. Surprisingly, reconstitution of the natural killer (NK) cell lineage, and particularly the major CD16(+)/CD56(-) peripheral blood NK compartment, showed limited clonal overlap with T, B, or myeloid lineages, and therefore appears to be ontologically distinct. Thus, in addition to providing insights into clonal behavior over time, our analysis suggests an unexpected paradigm for the relationship between NK cells and other hematopoietic lineages in primates.
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http://dx.doi.org/10.1016/j.stem.2014.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979461PMC
April 2014

Renal function in geriatric psychiatry patients compared to non-psychiatric older adults: effects of lithium use and other factors.

Aging Ment Health 2014 Sep 18;18(7):847-53. Epub 2014 Feb 18.

a Department of Psychiatry , McGill University , Montreal , Canada.

Objectives: Chronic renal failure is very common, affecting 30%-40% of community-dwelling elderly. We wished to verify whether geriatric psychiatry patients are at increased risk of renal dysfunction compared to elderly controls, as well as whether lithium exposure and other factors are important predictors of risk.

Method: This is a four-year retrospective cohort and nested case-control study at a Canadian tertiary-care hospital using data from March 2007 to March 2011. We compared 82 geriatric psychiatry outpatients and 200 psychotropic-naïve family medicine controls aged ≥65. Our main continuous measure of renal outcome was change in estimated glomerular filtration rate (eGFR). Multivariate analyses were performed to determine potential risk factors for renal dysfunction in geriatric psychiatry patients, including age, hypertension, diabetes mellitus, diuretics, and lithium duration.

Results: Clinically important decreases in eGFR (>8 mL/min/1.73 m(2)) were found in 40.2% of geriatric psychiatry patients compared to 29.5% of controls (p = 0.040). Multivariate analyses found that lithium duration was independently associated with adverse renal outcome in patients with eGFR < 60 mL/min/1.73 m(2). In this sub-population, lithium users had clinically important decreases in eGFR when compared to non-lithium users: 10.3 vs. 0.40 mL/min/1.73 m(2) (p = 0.017).

Conclusion: Geriatric psychiatry patients are at a greater risk for clinically important decreases of renal function than similarly aged controls. Lithium appears to be an important risk factor for renal dysfunction when eGFR is <60 mL/min/1.73 m(2). However, in the majority of older adults who have normal kidney function, lithium use appears to be safe.
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http://dx.doi.org/10.1080/13607863.2014.888536DOI Listing
September 2014