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Tumor-associated macrophage and T-cell subsets are implicated in the pathogenesis of diffuse large B-cell lymphoma, follicular lymphoma, and classical Hodgkin lymphoma. Macrophages provide essential mechanisms of tumor immune evasion through checkpoint ligand expression and secretion of suppressive cytokines. However, normal and tumor-associated macrophage phenotypes are less well characterized than those of tumor-infiltrating T-cell subsets, and it would be especially valuable to know whether the polarization state of macrophages differs across lymphoma tumor microenvironments. Here, an established mass cytometry panel designed to characterize myeloid-derived suppressor cells and known macrophage maturation and polarization states was applied to characterize B-lymphoma tumors and non-malignant human tissue. High-dimensional single-cell analyses were performed using dimensionality reduction and clustering tools. Phenotypically distinct intra-tumor macrophage subsets were identified based on abnormal marker expression profiles that were associated with lymphoma tumor types. While it had been proposed that measurement of CD163 and CD68 might be sufficient to reveal macrophage subsets in tumors, results here indicated that S100A9, CCR2, CD36, Slan, and CD32 should also be measured to effectively characterize lymphoma-specific tumor macrophages. Additionally, the presence of phenotypically distinct, abnormal macrophage populations was closely linked to the phenotype of intra-tumor T-cell populations, including PD-1 expressing T cells. These results further support the close links between macrophage polarization and T-cell functional state, as well as the rationale for targeting tumor-associated macrophages in cancer immunotherapies.
BACKGROUND - Circulating biomarkers can facilitate diagnosis and risk stratification for complex conditions such as heart failure (HF). Newer molecular platforms can accelerate biomarker discovery, but they require significant resources for data and sample acquisition.
OBJECTIVES - The purpose of this study was to test a pragmatic biomarker discovery strategy integrating automated clinical biobanking with proteomics.
METHODS - Using the electronic health record, the authors identified patients with and without HF, retrieved their discarded plasma samples, and screened these specimens using a DNA aptamer-based proteomic platform (1,129 proteins). Candidate biomarkers were validated in 3 different prospective cohorts.
RESULTS - In an automated manner, plasma samples from 1,315 patients (31% with HF) were collected. Proteomic analysis of a 96-patient subset identified 9 candidate biomarkers (p < 4.42 × 10). Two proteins, angiopoietin-2 and thrombospondin-2, were associated with HF in 3 separate validation cohorts. In an emergency department-based registry of 852 dyspneic patients, the 2 biomarkers improved discrimination of acute HF compared with a clinical score (p < 0.0001) or clinical score plus B-type natriuretic peptide (p = 0.02). In a community-based cohort (n = 768), both biomarkers predicted incident HF independent of traditional risk factors and N-terminal pro-B-type natriuretic peptide (hazard ratio per SD increment: 1.35 [95% confidence interval: 1.14 to 1.61; p = 0.0007] for angiopoietin-2, and 1.37 [95% confidence interval: 1.06 to 1.79; p = 0.02] for thrombospondin-2). Among 30 advanced HF patients, concentrations of both biomarkers declined (80% to 84%) following cardiac transplant (p < 0.001 for both).
CONCLUSIONS - A novel strategy integrating electronic health records, discarded clinical specimens, and proteomics identified 2 biomarkers that robustly predict HF across diverse clinical settings. This approach could accelerate biomarker discovery for many diseases.
Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4 and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1α or of both HIF-1α and HIF-2α in CD4 T cells compromised essential functions in help during antibody responses. HIF-1α depletion from CD4 T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab after immunization with sheep red blood cells. Compound deficiency of HIF-1α and HIF-2α led to humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4 cells in the CXCR5 follicular regulatory population. Glycolysis increases T helper cytokine expression, and HIF promoted glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, IFN-γ elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of help during humoral responses.
Repeatability and reproducibility of magnetization transfer magnetic resonance imaging of the breast, and the ability of this technique to assess the response of locally advanced breast cancer to neoadjuvant therapy (NAT), are determined. Reproducibility scans at 3 different 3 T scanners, including 2 scanners in community imaging centers, found a 16.3% difference (n = 3) in magnetization transfer ratio (MTR) in healthy breast fibroglandular tissue. Repeatability scans (n = 10) found a difference of ∼8.1% in the MTR measurement of fibroglandular tissue between the 2 measurements. Thus, MTR is repeatable and reproducible in the breast and can be integrated into community imaging clinics. Serial magnetization transfer magnetic resonance imaging performed at longitudinal time points during NAT indicated no significant change in average tumoral MTR during treatment. However, histogram analysis indicated an increase in the dispersion of MTR values of the tumor during NAT, as quantified by higher standard deviation ( = .005), higher full width at half maximum ( = .02), and lower kurtosis ( = .02). Patients' stratification into those with pathological complete response (pCR; n = 6) at the conclusion of NAT and those with residual disease (n = 9) showed wider distribution of tumor MTR values in patients who achieved pCR after 2-4 cycles of NAT, as quantified by higher standard deviation ( = .02), higher full width at half maximum ( = .03), and lower kurtosis ( = .03). Thus, MTR can be used as an imaging metric to assess response to breast NAT.
CD40 expression is required for germinal center (GC) formation and function, but the kinetics and magnitude of signaling following CD40 engagement remain poorly characterized in human B cells undergoing GC reactions. Here, differences in CD40 expression and signaling responses were compared across differentiation stages of mature human tonsillar B cells. A combination of mass cytometry and phospho-specific flow cytometry was used to quantify protein expression and CD40L-induced signaling in primary human naïve, GC, and memory B cells. Protein expression signatures of cell subsets were quantified using viSNE and Marker Enrichment Modeling (MEM). This approach revealed enriched expression of CD40 protein in GC B cells, compared to naïve and memory B cells. Despite this, GC B cells responded to CD40L engagement with lower phosphorylation of NFκB p65 during the first 30 min following CD40L activation. Before CD40L stimulation, GC B cells expressed higher levels of suppressor protein IκBα than naïve and memory B cells. Following CD40 activation, IκBα was rapidly degraded and reached equivalently low levels in naïve, GC, and memory B cells at 30 min following CD40L. Quantifying CD40 signaling responses as a function of bound ligand revealed a correlation between bound CD40L and degree of induced NFκB p65 phosphorylation, whereas comparable IκBα degradation occurred at all measured levels of CD40L binding. These results characterize cell-intrinsic signaling differences that exist in mature human B cells undergoing GC reactions. © 2019 International Society for Advancement of Cytometry.
© 2019 International Society for Advancement of Cytometry.
OBJECTIVES - We sought to validate the use of crowdsourced surgical video assessment in the evaluation of urology residents performing flexible ureteroscopic laser lithotripsy.
METHODS - We collected video feeds from 30 intrarenal ureteroscopic laser lithotripsy cases where residents, postgraduate year (PGY) two through six, handled the ureteroscope. The video feeds were annotated to represent overall performance and to contain parts of the procedure being scored. Videos were submitted to a commercially available surgical video evaluation platform (Crowd-Sourced Assessment of Technical Skills). We used a validated ureteroscopic laser lithotripsy global assessment tool that was modified to include only those domains that could be evaluated on the captured video. Videos were evaluated by crowd workers recruited using Amazon's Mechanical Turk platform as well as five endourology-trained experts. Mean scores were calculated and intraclass correlation coefficients (ICCs) were computed for the expert domain and total scores. ICCs were estimated using a linear mixed-effects model. Spearman rank correlation coefficients were calculated as a measure of the strength of the relationships between the crowd mean and expert average scores.
RESULTS - A total of 30 videos were reviewed 2488 times by 487 crowd workers and five expert endourologists. ICCs between expert raters were all below accepted levels of correlation (0.30), with the overall score having an ICC of <0.001. For individual domains, the crowd scores did not correlate with expert scores, except for the stone retrieval domain (0.60 p = 0.015). In addition, crowdsourced scores had a negative correlation with the PGY level (0.44, p = 0.019).
CONCLUSIONS - There is poor agreement between experts and poor correlation between expert and crowd scores when evaluating video feeds of ureteroscopic laser lithotripsy. The use of an intraoperative video of ureteroscopy with laser lithotripsy for assessment of resident trainee skills does not appear reliable. This is further supported by the lack of correlation between crowd scores and advancing PGY level.
INTRODUCTION - Idiopathic subglottic stenosis (iSGS) is an unexplained progressive obstruction of the upper airway that occurs almost exclusively in adult, Caucasian women. The disease is characterised by mucosal inflammation and localised fibrosis resulting in life-threatening blockage of the upper airway. Because of high recurrence rates, patients with iSGS will frequently require multiple procedures following their initial diagnosis. Both the disease and its therapies profoundly affect patients' ability to breathe, communicate and swallow. A variety of treatments have been advanced to manage this condition. However, comparative data on effectiveness and side effects of the unique approaches have never been systematically evaluated. This study will create an international, multi-institutional prospective cohort of patients with iSGS. It will compare three surgical approaches to determine how well the most commonly used treatments in iSGS 'work' and what quality of life (QOL) trade-offs are associated with each approach.
METHODS AND ANALYSIS - A prospective pragmatic trial comparing the 'Standard of Care' for iSGS at multiple international institutions. Patients with a diagnosis of iSGS without clinical or laboratory evidence of vasculitis or a history of endotracheal intubation 2 years prior to symptom onset will be included in the study. Prospective evaluation of disease recurrence requiring operative intervention, validated patient-reported outcome (PRO) measures as well as patient-generated health data (mobile peak flow recordings and daily steps taken) will be longitudinally tracked for 36 months. The primary endpoint is treatment effectiveness defined as time to recurrent operative procedure. Secondary endpoints relate to treatment side effects and include PRO measures in voice, swallowing, breathing and global QOL as well as patient-generated health data.
ETHICS AND DISSEMINATION - This protocol was approved by the local IRB Committee of the Vanderbilt University Medical Center in July 2015. The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations and directly to patient with iSGS via social media-based support groups.
TRIAL REGISTRATION NUMBER - NCT02481817.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PURPOSE - Academic scientists work in competitive environments, and many institutions invest in career development supports. These investments may be imperiled when extraprofessional demands challenge a faculty member's reserve capacity. This research assessed prevalence of caregiving challenges and estimated incidence of stressful life events.
METHOD - In 2015-2016, the authors surveyed recipients of career development awards supporting ≥ 75% effort and individuals within the funding period of their first National Institutes of Health R01 or equivalent at Vanderbilt University Medical Center. Domains included family structure, hospitalizations of family members, responsibility for coordination of caregiving, and an inventory of stressful life events.
RESULTS - Seventy-two percent (152 of 210) of early career researchers responded. Over half endorsed experiencing one or more substantial caregiving challenges in the prior year. This included 35 (23%) having a child or adult in the household hospitalized in the prior year and 36 (24%) being responsible for health care needs for a child or adult in the household, or for coordinating elder care, assisted living, or hospice care. The majority experienced one or more caregiving challenges. Stressful life events increased relative risk of "thinking about leaving academics" by 70% (risk ratio: 1.7; 95% confidence interval: 1.2, 2.4). Prevalence and incidence of caregiving demands did not differ by gender.
CONCLUSIONS - Leaders, administrators, mentors, and faculty should anticipate that most women and men early career researchers will experience substantial caregiving challenges and life events in any given year. Sufficient need exists to warrant investigation of institutional programs to address caregiving challenges.
B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.
Copyright © 2018 by The American Association of Immunologists, Inc.
Background - Trauma-related hospitalizations drive a high percentage of health care expenditure and inpatient resource consumption, which is directly related to length of stay (LOS). Robust and reliable interactions among health care employees can reduce LOS. However, there is little known about whether certain patterns of interactions exist and how they relate to LOS and its variability. The objective of this study is to learn interaction patterns and quantify the relationship to LOS within a mature trauma system and long-standing electronic medical record (EMR).
Methods - We adapted a spectral co-clustering methodology to infer the interaction patterns of health care employees based on the EMR of 5588 hospitalized adult trauma survivors. The relationship between interaction patterns and LOS was assessed via a negative binomial regression model. We further assessed the influence of potential confounders by age, number of health care encounters to date, number of access action types care providers committed to patient EMRs, month of admission, phenome-wide association study codes, procedure codes, and insurance status.
Results - Three types of interaction patterns were discovered. The first pattern exhibited the most collaboration between employees and was associated with the shortest LOS. Compared to this pattern, LOS for the second and third patterns was 0.61 days (P = 0.014) and 0.43 days (P = 0.037) longer, respectively. Although the 3 interaction patterns dealt with different numbers of patients in each admission month, our results suggest that care was provided for similar patients.
Discussion - The results of this study indicate there is an association between LOS and the extent to which health care employees interact in the care of an injured patient. The findings further suggest that there is merit in ascertaining the content of these interactions and the factors that induce these differences in interaction patterns within a trauma system.