M-CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors. VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation ...and new blood vessel formation. Previously, we reported that in vitro M-CSF induces the expression of biologically-active VEGF from human monocytes.
In this study, we demonstrate the molecular mechanism of M-CSF-induced VEGF production. Using a construct containing the VEGF promoter linked to a luciferase reporter, we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M-CSF stimulation. Further analysis revealed that M-CSF induced VEGF through the MAPK/ERK signaling pathway via the transcription factor, Sp1. Thus, inhibition of either ERK or Sp1 suppressed M-CSF-induced VEGF at the mRNA and protein level. M-CSF also induced the nuclear localization of Sp1, which was blocked by ERK inhibition. Finally, mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M-CSF-treated human monocytes. To evaluate the biological significance of M-CSF induced VEGF production, we used an in vivo angiogenesis model to illustrate the ability of M-CSF to recruit mononuclear phagocytes, increase VEGF levels, and enhance angiogenesis. Importantly, the addition of a neutralizing VEGF antibody abolished M-CSF-induced blood vessel formation.
These data delineate an ERK- and Sp1-dependent mechanism of M-CSF induced VEGF production and demonstrate for the first time the ability of M-CSF to induce angiogenesis via VEGF in vivo.
Most patients with restriction have a pulmonary function test (PFT) pattern in which total lung capacity (TLC), FVC, and FEV
are reduced to a similar degree. This pattern is called "simple ...restriction" (SR). In contrast, we commonly observe a pattern in which FVC percent predicted (
) is disproportionately reduced relative to TLC
. This pattern is termed "complex restriction" (CR), and we attempted to characterize its clinical, radiologic, and physiologic features.
This study reviewed PFT results of patients tested between November 2009 and June 2013 who had restriction (TLC less than the lower limit of normal). SR was defined as TLC
-FVC
≤ 10%, and CR was stratified into four classes based on TLC
-FVC
discrepancy: Class 1 CR, TLC
-FVC
> 10% and ≤ 15%; Class 2 CR, TLC
-FVC
> 15% and ≤20%; Class 3 CR, TLC
-FVC
> 20% and ≤ 25%; and Class 4 CR, TLC
-FVC
> 25%. The medical records of 150 randomly selected patients with SR and 50 patients from each CR class were reviewed.
Of 39,277 PFTs completed, we identified 4,532 patients (11.5%) with restriction: 2,407 (6.1%) with SR, 1,614 (4.1%) with CR, and 511 (1.3%) with a mixed pattern. Patients with CR were younger, were more often women, and had a higher prevalence of neuromuscular disease, BMI > 40 kg/m
or < 18.5 kg/m
, diaphragmatic dysfunction, bronchiectasis, CT mosaic attenuation, and pulmonary hypertension (P < .0001, < .0001, < .001, .004, .0008, .002, .008, .009, .053, and .01, respectively) and a lower prevalence of interstitial lung disease (P < .0001).
CR is a common PFT pattern with distinct clinical features. The associated clinical entities share impaired lung emptying (eg, neuromuscular disease, occult obstruction, chest wall limitation). Clinicians should be aware of this novel PFT pattern and how it shapes the differential diagnosis.
Background and Objectives: Patients with pre-existing cardiac disease have a higher prevalence of Obstructive Sleep Apnea (OSA). OSA has been associated with an increased risk of supraventricular and ...ventricular arrhythmia. We screened subjects with implanted pacemakers and automated implantable cardioverter defibrillators (AICD) for OSA with the Berlin Questionnaire and compared the incidence of ventricular arrhythmias and automated implantable cardioverter defibrillator (AICD) firing between high and low OSA risk groups. Materials and Methods: We contacted 648 consecutive patients from our arrhythmia clinic to participate in the study and performed final analyses on 171 subjects who consented and had follow-up data. Data were abstracted from the electronic health record for the incidence of non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT), ventricular fibrillation (VF) and AICD firing and then compared between those at high versus low risk of OSA using the Berlin Questionnaire and multivariate negative binomial regression. Results: The average follow-up period was 24.2 ± 4.4 months. After adjusting for age, gender and history of heart failure, those subjects at high risk of OSA had a higher burden of NSVT vs. those with a low risk of OSA (33.4 ± 96.2 vs. 5.82 ± 17.1 episodes, p = 0.003). A predetermined subgroup analysis of AICD recipients also demonstrated a significantly higher burden of NSVT in the high vs. low OSA risk groups (66.2 ± 128.6 vs. 18.9 ± 36.7 episodes, p = 0.033). There were significant differences in the rates of VT, VF or AICD shock burden between the high and low OSA risk groups and in the AICD subgroup analysis. Conclusions: There was increased ventricular ectopy among pacemaker and AICD recipients at high risk of OSA, but the prevalence of VT, VF or AICD shocks was similar to those with low risk of OSA.
Lung adenocarcinoma (ADC), the most common lung cancer type, is recognized increasingly as a disease spectrum. To guide individualized patient care, a non-invasive means of distinguishing indolent ...from aggressive ADC subtypes is needed urgently. Computer-Aided Nodule Assessment and Risk Yield (CANARY) is a novel computed tomography (CT) tool that characterizes early ADCs by detecting nine distinct CT voxel classes, representing a spectrum of lepidic to invasive growth, within an ADC. CANARY characterization has been shown to correlate with ADC histology and patient outcomes. This study evaluated the inter-observer variability of CANARY analysis. Three novice observers segmented and analyzed independently 95 biopsy-confirmed lung ADCs from Vanderbilt University Medical Center/Nashville Veterans Administration Tennessee Valley Healthcare system (VUMC/TVHS) and the Mayo Clinic (Mayo). Inter-observer variability was measured using intra-class correlation coefficient (ICC). The average ICC for all CANARY classes was 0.828 (95% CI 0.76, 0.895) for the VUMC/TVHS cohort, and 0.852 (95% CI 0.804, 0.901) for the Mayo cohort. The most invasive voxel classes had the highest ICC values. To determine whether nodule size influenced inter-observer variability, an additional cohort of 49 sub-centimeter nodules from Mayo were also segmented by three observers, with similar ICC results. Our study demonstrates that CANARY ADC classification between novice CANARY users has an acceptably low degree of variability, and supports the further development of CANARY for clinical application.
Tumor-educated macrophages facilitate tumor metastasis and angiogenesis. We discovered that granulocyte macrophage colony-stimulating factor (GM-CSF) blocked macrophages vascular endothelial growth ...factor (VEGF) activity by producing soluble VEGF receptor-1 (sVEGFR-1) and determined the effect on tumor-associated macrophage behavior and tumor growth. We show GM-CSF treatment of murine mammary tumors slowed tumor growth and slowed metastasis. These tumors had more macrophages, fewer blood vessels, and lower oxygen concentrations. This effect was sVEGFR-1 dependent. In situ hybridization and flow cytometry identified macrophages as the primary source of sVEGFR-1. These data suggest that GM-CSF can re-educate macrophages to reduce angiogenesis and metastases in murine breast cancer.
Data examining associations among social support, survival, and healthcare utilization are lacking in patients with advanced cancer.
We conducted a cross-sectional secondary analysis using data from ...a prospective longitudinal cohort study of 966 hospitalized patients with advanced cancer at Massachusetts General Hospital from 2014 through 2017. We used NLP to identify extent of patients' social support (limited versus adequate as defined by NLP-aided review of the Electronic Health Record (EHR)). Two independent coders achieved a Kappa of 0.90 (95% CI: 0.84-1.00) using NLP. Using multivariable regression models, we examined associations of social support with: 1) OS; 2) death or readmission within 90 days of hospital discharge; 3) time to readmission within 90 days; and 4) hospital length of stay (LOS).
Patients' median age was 65 (range: 21-92) years, and a plurality had gastrointestinal (GI) cancer (34.3%) followed by lung cancer (19.5%). 6.2% (60/966) of patients had limited social support. In multivariable analyses, limited social support was not significantly associated with OS (HR = 1.13, P = 0.390), death or readmission (OR = 1.18, P = 0.578), time to readmission (HR = 0.92, P = 0.698), or LOS (β = -0.22, P = 0.726). We identified a potential interaction suggesting cancer type (GI cancer versus other) may be an effect modifier of the relationship between social support and OS (interaction term P = 0.053). In separate unadjusted analyses, limited social support was associated with lower OS (HR = 2.10, P = 0.008) in patients with GI cancer but not other cancer types (HR = 1.00, P = 0.991).
We used NLP to assess the extent of social support in patients with advanced cancer. We did not identify significant associations of social support with OS or healthcare utilization but found cancer type may be an effect modifier of the relationship between social support and OS. These findings underscore the potential utility of NLP for evaluating social support in patients with advanced cancer.
PURPOSE:This study assessed a novel diabetes mellitus (DM) rating scale in relation to its utility in reducing Descemet membrane endothelial keratoplasty (DMEK) tissue preparation failure.
METHODS:A ...5-point DM rating scale was defined, in which 1 demonstrated relatively good health associated with DM and 5 represented comorbidities associated with DM. A chart review from consecutive donors who had at least 1 tissue prepared for DMEK was performed. Using the donor profile, the first tissue processed from each donor was categorized according to the DM severity and if the tissue passed or failed the DMEK preparation. Failure rates per rating group were evaluated using logistic regression and odds of preparation failure.
RESULTS:A total of 125 tissues prepared for DMEK were categorized based on the defined DM rating scale. Of these, 9 tissues were rated 1 (11.1% failure), 25 were rated 2 (0% failure), 31 were rated 3 (6.5% failure), 24 were rated 4 (16.7% failure), and 36 were rated 5 (30.6% failure). The odds ratios were significant for tissues rated as 5 and 3 (P < 0.05). No other rating categories were found to influence the odds of failure. A χ test comparing categories of low risk (1–3) and high risk (4–5) was also performed (P = 0.001).
CONCLUSIONS:The DM rating scale does seem to stratify the risk of preparation failure associated with the severity of DM and associated comorbidities. Inclusion of some diabetic donors for the preparation of DMEK grafts may be warranted given proper screening of the donor history and application of the rating scale.
Most patients with restriction have a pulmonary function test (PFT) pattern in which total lung capacity (TLC), FVC, and FEV1 are reduced to a similar degree. This pattern is called “simple ...restriction” (SR). In contrast, we commonly observe a pattern in which FVC percent predicted (pp) is disproportionately reduced relative to TLCpp. This pattern is termed “complex restriction” (CR), and we attempted to characterize its clinical, radiologic, and physiologic features.
This study reviewed PFT results of patients tested between November 2009 and June 2013 who had restriction (TLC less than the lower limit of normal). SR was defined as TLCpp-FVCpp ≤ 10%, and CR was stratified into four classes based on TLCpp-FVCpp discrepancy: Class 1 CR, TLCpp-FVCpp > 10% and ≤ 15%; Class 2 CR, TLCpp-FVCpp > 15% and ≤20%; Class 3 CR, TLCpp-FVCpp > 20% and ≤ 25%; and Class 4 CR, TLCpp-FVCpp > 25%. The medical records of 150 randomly selected patients with SR and 50 patients from each CR class were reviewed.
Of 39,277 PFTs completed, we identified 4,532 patients (11.5%) with restriction: 2,407 (6.1%) with SR, 1,614 (4.1%) with CR, and 511 (1.3%) with a mixed pattern. Patients with CR were younger, were more often women, and had a higher prevalence of neuromuscular disease, BMI > 40 kg/m2 or < 18.5 kg/m2, diaphragmatic dysfunction, bronchiectasis, CT mosaic attenuation, and pulmonary hypertension (P < .0001, < .0001, < .001, .004, .0008, .002, .008, .009, .053, and .01, respectively) and a lower prevalence of interstitial lung disease (P < .0001).
CR is a common PFT pattern with distinct clinical features. The associated clinical entities share impaired lung emptying (eg, neuromuscular disease, occult obstruction, chest wall limitation). Clinicians should be aware of this novel PFT pattern and how it shapes the differential diagnosis.
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